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Simple Sugar and Sugar-Sweetened Beverage Intake During Adolescence and Risk of Colorectal Cancer Precursors

  • Hee-Kyung Joh
    Correspondence
    Correspondence Address correspondence to: Hee-Kyung Joh, MD, MPH, PhD, Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building II, Room 359, Boston, Massachusetts 02115.
    Affiliations
    Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Dong Hoon Lee
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Jinhee Hur
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Katharina Nimptsch
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
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  • Yoosoo Chang
    Affiliations
    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
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  • Hyojee Joung
    Affiliations
    Department of Public Health, Graduate School of Public Health and Institute of Health and Environment, Seoul National University, Gwanak-gu, Seoul, Republic of Korea
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  • Xuehong Zhang
    Affiliations
    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Leandro F.M. Rezende
    Affiliations
    Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Medicina Preventiva, São Paulo, SP, Brazil
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  • Jung Eun Lee
    Affiliations
    Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Republic of Korea

    Research Institute of Human Ecology, Seoul National University, Gwanak-gu, Seoul, Republic of Korea
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  • Kimmie Ng
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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  • Chen Yuan
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Fred K. Tabung
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio
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  • Jeffrey A. Meyerhardt
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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  • Andrew T. Chan
    Affiliations
    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Tobias Pischon
    Affiliations
    Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
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  • Mingyang Song
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Charles S. Fuchs
    Affiliations
    Yale Cancer Center, Department of Medicine, Yale School of Medicine and Smilow Cancer Hospital, New Haven, Connecticut
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  • Walter C. Willett
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors contributed equally.
    Yin Cao
    Footnotes
    ∗ Authors contributed equally.
    Affiliations
    Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

    Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
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  • Author Footnotes
    ∗ Authors contributed equally.
    Shuji Ogino
    Footnotes
    ∗ Authors contributed equally.
    Affiliations
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors contributed equally.
    Edward Giovannucci
    Footnotes
    ∗ Authors contributed equally.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors contributed equally.
    Kana Wu
    Footnotes
    ∗ Authors contributed equally.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors contributed equally.

      Background & aims

      Recent increasing trends in early-onset colorectal cancer (CRC) strongly supports that early-life diet is involved in CRC development. However, data are lacking on the relationship with high sugar intake during early life.

      Methods

      We prospectively investigated the association of adolescent simple sugar (fructose, glucose, added sugar, total sugar) and sugar-sweetened beverage (SSB) intake with CRC precursor risk in 33,106 participants of the Nurses’ Health Study II who provided adolescent dietary information in 1998 and subsequently underwent lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data.

      Results

      During follow-up, 2909 conventional adenomas (758 high-risk) and 2355 serrated lesions were identified (mean age at diagnoses, 52.2 ± 4.3 years). High sugar and SSB intake during adolescence was positively associated with risk of adenoma, but not serrated lesions. Per each increment of 5% of calories from total fructose intake, multivariable ORs were 1.17 (95% CI, 1.05–1.31) for total and 1.30 (95% CI, 1.06–1.60) for high-risk adenoma. By subsite, ORs were 1.12 (95% CI, 0.96–1.30) for proximal, 1.24 (95% CI, 1.05–1.47) for distal, and 1.43 (95% CI, 1.10–1.86) for rectal adenoma. Per 1 serving/day increment in SSB intake, ORs were 1.11 (95% CI, 1.02–1.20) for total and 1.30 (95% CI, 1.08–1.55) for rectal adenoma. Contrary to adolescent intake, sugar and SSB intake during adulthood was not associated with adenoma risk.

      Conclusions

      High intake of simple sugars and SSBs during adolescence was associated with increased risk of conventional adenoma, especially rectal adenoma.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      ASB (artificially sweetened beverages), BMI (body mass index), CI (confidence interval), CRC (colorectal cancer), DGA (Dietary Guidelines for Americans), HS-FFQ (high school food frequency questionnaire), IGF1 (insulin-like growth factor 1), OR (odds ratio), SSB (sugar-sweetened beverage)
      See editorial on page 27.

       Background and Context

      Recent increasing trends in early-onset colorectal cancer strongly supports that early-life diet is involved in colorectal cancer development. However, evidence is lacking on the relationship between sugar intake during early-life and colorectal neoplasia.

       New Findings

      High intake of simple sugars and sugar-sweetened beverages during adolescence was significantly associated with increased risk of conventional adenoma, especially rectal adenoma, but not serrated lesions. Neither sugar nor sugar-sweetened beverage intake during adulthood was associated with adenoma risk.

       Limitations

      The study population consisted of predominantly white female nurses.

       Impact

      Given the profound increase in added sugar and sugar-sweetened beverage intake during the past several decades, our findings may partly explain the current upward trends in early-onset colorectal cancer.
      The global burden of colorectal cancer (CRC) is expected to increase to more than 2.2 million new cases and 1.1 million cancer deaths per annum by 2030.
      • Arnold M.
      • Sierra M.S.
      • Laversanne M.
      • et al.
      Global patterns and trends in colorectal cancer incidence and mortality.
      In many high-income countries, the burden of CRC is rapidly shifting to younger individuals.
      • Siegel R.L.
      • Jakubowski C.D.
      • Fedewa S.A.
      • et al.
      Colorectal cancer in the young: epidemiology, prevention, management.
      • Keum N.
      • Giovannucci E.
      Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
      • Siegel R.L.
      • Miller K.D.
      • Goding Sauer A.
      • et al.
      Colorectal cancer statistics, 2020.
      In the United States, despite declines in older adults, incidence is increasing in young and middle-aged adults with 22% of CRC cases occurring in those younger than 55 years in 2013 to 2017.
      • Siegel R.L.
      • Miller K.D.
      • Goding Sauer A.
      • et al.
      Colorectal cancer statistics, 2020.
      ,

      SEER Cancer Stat Facts: CRC. Bethesda, MD: National Cancer Institute. Available at seer.cancer.gov/statfacts/html/colorect.html. Accessed Oct 12, 2020.

      CRC incidence has been on the rise among young adults aged 20 to 39 years since the mid-1980s, among those aged <50 years since the mid-1990s, and among those aged 50 to 64 years since 2011.
      • Siegel R.L.
      • Miller K.D.
      • Goding Sauer A.
      • et al.
      Colorectal cancer statistics, 2020.
      ,
      American Cancer Society
      Colorectal Cancer Facts & Figures 2020–2022.
      This birth cohort effect (elevated risk in generations born after 1950) strongly indicates that population-level changes in early-life exposures, such as diet and lifestyle factors, may explain the upward trend in early-onset CRC.
      • Siegel R.L.
      • Jakubowski C.D.
      • Fedewa S.A.
      • et al.
      Colorectal cancer in the young: epidemiology, prevention, management.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Goding Sauer A.
      • et al.
      Colorectal cancer statistics, 2020.
      Simple sugar, especially added fructose, intake has steeply increased in recent decades largely due to the marked increase in sugar-sweetened beverage (SSB) intake.
      • Bray G.A.
      • Nielsen S.J.
      • Popkin B.M.
      Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
      ,
      • Marriott B.P.
      • Cole N.
      • Lee E.
      National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.
      SSBs (carbonated and noncarbonated soft drinks, fruit drinks, and sports drinks) are mostly sweetened with high-fructose corn syrup (usually 55% fructose and 45% glucose) or sucrose (half fructose and half glucose).
      • Bray G.A.
      • Nielsen S.J.
      • Popkin B.M.
      Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
      In the United States, SSB availability has risen dramatically since the 1950s.

      Healthy Food America. Sugary drinks in America: who's drinking what and how much? Available at healthyfoodamerica.org/sugary_drinks_in_america_who_s_drinking_what_and_how_much. Accessed Oct 21, 2020.

      Between 1965 and 1996, SSB intake among US adolescents more than doubled (per capita g/d: boys 364 to 1046, girls 303 to 678).
      • Cavadini C.
      • Siega-Riz A.M.
      • Popkin B.M.
      US adolescent food intake trends from 1965 to 1996.
      Compared with other age groups, adolescents had the highest SSB intake with approximately 10% of daily calories from SSBs in 2011 to 2014.
      • Rosinger A.
      • Herrick K.
      • Gahche J.
      • et al.
      Sugar-sweetened beverage consumption among U.S. youth, 2011–2014.
      SSB consumption is also rapidly increasing worldwide, particularly in developing countries.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      In 53 low- and middle-income countries, 54% of adolescents consumed carbonated soft drinks at least once per day in 2009 to 2013.
      • Yang L.
      • Bovet P.
      • Liu Y.
      • et al.
      Consumption of carbonated soft drinks among young adolescents aged 12 to 15 years in 53 low- and middle-income countries.
      High sugar intake can promote colorectal carcinogenesis by causing insulin resistance, obesity, and type 2 diabetes
      • Yu Z.
      • Ley S.H.
      • Sun Q.
      • et al.
      Cross-sectional association between sugar-sweetened beverage intake and cardiometabolic biomarkers in US women.
      : established risk factors for CRC.
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      Despite the close link between insulin resistance and CRC,
      • Giovannucci E.
      Insulin, insulin-like growth factors and colon cancer: a review of the evidence.
      ,
      • Kaaks R.
      • Toniolo P.
      • Akhmedkhanov A.
      • et al.
      Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women.
      most prospective studies have reported null associations between adult sugar intake and colorectal neoplasia.
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      ,
      • Zhang X.
      • Albanes D.
      • Beeson W.L.
      • et al.
      Risk of colon cancer and coffee, tea, and sugar-sweetened soft drink intake: pooled analysis of prospective cohort studies.
      ,
      Imperial College London Continuous Update Project
      World Cancer Research Fund International Systematic Literature Review: The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer.
      However, data are lacking on the association of high sugar intake during early life. Considering the long process of carcinogenesis generally spanning several decades and recent upward trends in early-onset CRC,
      • Siegel R.L.
      • Jakubowski C.D.
      • Fedewa S.A.
      • et al.
      Colorectal cancer in the young: epidemiology, prevention, management.
      ,
      • Keum N.
      • Giovannucci E.
      Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
      early-life diet may be etiologically relevant to CRC development.
      • Nimptsch K.
      • Wu K.
      Is timing important? The role of diet and lifestyle during early life on colorectal neoplasia.
      Moreover, adolescence is a unique growth period characterized by physiologically decreased insulin sensitivity and a surge in insulin-like growth factor 1 (IGF1).
      • Hannon T.S.
      • Janosky J.
      • Arslanian S.A.
      Longitudinal study of physiologic insulin resistance and metabolic changes of puberty.
      Thus, adolescence may be a critical period of enhanced susceptibility to the adverse effects of high sugar consumption.
      Our hypothesis was that high sugar intake during adolescence may play a role in development of CRC precursors, which are the early steps of colorectal carcinogenesis and primary targets of screening colonoscopy for early intervention.
      • Keum N.
      • Giovannucci E.
      Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
      ,
      • Strum W.B.
      Colorectal adenomas.
      We prospectively investigated the association of adolescent simple sugar and SSB intake with risk of colorectal polyps in a large cohort of young women.

      Methods

       Study Population

      The Nurses’ Health Study II is an ongoing prospective cohort established in 1989 when 116,430 US female registered nurses aged 25 to 42 years returned a mailed questionnaire about various lifestyle factors and medical history.
      • Bao Y.
      • Bertoia M.L.
      • Lenart E.B.
      • et al.
      Origin, methods, and evolution of the three nurses' health studies.
      Follow-up questionnaires were mailed biennially to update the information and newly diagnosed diseases. We included women who had completed a high school Food Frequency Questionnaire (HS-FFQ)
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      about adolescent diet in 1998 and subsequently underwent at least 1 lower gastrointestinal endoscopy between 1999 and 2015. We excluded women who had no lower bowel endoscopy during the follow-up because colorectal polyps are generally asymptomatic and detected during an endoscopy. We also excluded women with a history of any cancer (other than nonmelanoma skin cancer), colorectal polyps, Crohn's disease, or ulcerative colitis before the return of the HS-FFQ, and those reporting implausible adolescent caloric intake (<600 or >5000 kcal/d) or extensive missing responses (>70 for food items or ≥2 sections entirely blank other than dairy and eggs/meat sections), leaving a total of 33,106 women for the current analyses. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required.

       Dietary Assessment

      Adolescent diet was assessed using a 124-item self-administered HS-FFQ, specifically designed to include food items commonly consumed between 1960 and 1982 when participants were 13 to 18 years.
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      Participants were asked how often, on average, they had consumed a standard portion size of each food or beverage when they were in high school, with 9 possible responses ranging from “never or less than once per month” to “6 or more times per day.” The reproducibility and validity of the HS-FFQ have been previously described in detail.
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      ,
      • Maruti S.S.
      • Feskanich D.
      • Rockett H.R.
      • et al.
      Validation of adolescent diet recalled by adults.
      In brief, reproducibility at a 4-year interval was moderate-to-good (correlation for overall nutrients, r = 0.65; foods, 0.60; total fructose, 0.65; cola, 0.74; orange juice, 0.74).
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      In a validation study comparing dietary measures collected in 80 adolescents (aged 13–18 years) with the HS-FFQ completed 10 years later in the same youths, adequate validity was reported (r for overall nutrients, 0.58; total fructose, 0.44).
      • Maruti S.S.
      • Feskanich D.
      • Rockett H.R.
      • et al.
      Validation of adolescent diet recalled by adults.
      Since 1991, adult diet was assessed every 4 years using a validated FFQ with approximately 131 food items.
      • Hu F.B.
      • Rimm E.
      • Smith-Warner S.A.
      • et al.
      Reproducibility and validity of dietary patterns assessed with a food-frequency questionnaire.
      Total fructose intake was defined as the sum of free fructose and half of sucrose intake because sucrose consists of half fructose and half glucose.
      • Bray G.A.
      • Nielsen S.J.
      • Popkin B.M.
      Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
      Likewise, glucose intake from simple sugars was defined as the sum of free glucose and half of sucrose intake. Added sugar referred to sugar added to foods and beverages during processing or preparation.
      • Johnson R.K.
      • Appel L.J.
      • Brands M.
      • et al.
      Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.
      Total sugar represented the sum of free fructose, free glucose, sucrose, and maltose. SSBs were defined as caffeinated and caffeine-free colas (eg, Coke, Pepsi) and other carbonated (eg, 7-Up) and noncarbonated sugary beverages (fruit punches, lemonades, or other fruit drinks). Artificially sweetened beverages (ASBs) included carbonated and noncarbonated low-calorie or diet beverages. Standard serving sizes for SSBs and ASBs were 1 glass, a bottle, or a can (12 ounces). Fruit juice included orange, apple, grapefruit, and other fruit juices, with 1 small glass (6 ounces) as a serving size. Dairy products included milk, yogurt, cheese, ice cream, sherbet, milkshake, and frappe.
      The nutrient database corresponding to each questionnaire cycle was primarily derived from US Department of Agriculture sources and supplemented with information from manufacturers.
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      ,
      US Department of Agriculture
      Composition of foods: raw, processed, and prepared, 1963–1980. (Agricultural handbook no. 8).
      Nutrient intake was adjusted for total energy intake using the residual method.
      • Willett W.
      Nutritional epidemiology.
      ,
      • Willett W.
      • Stampfer M.J.
      Total energy intake: implications for epidemiologic analyses.
      For sugar intake, we also calculated nutrient density (percentage of daily calories contributed by each sugar) because most current dietary recommendations for added sugar intake are based on percentage of total calorie intake (eg, the 2015–2020 and 2020–2025 Dietary Guidelines for Americans [DGA] have recommended limiting added sugar intake to <10% of total calories per day).
      • Johnson R.K.
      • Appel L.J.
      • Brands M.
      • et al.
      Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.
      ,
      U.S. Department of Agriculture and U.S. Department of Health and Human Services
      Dietary guidelines for Americans, 2020–2025.
      We considered changes in diet over time during follow-up, including simple sugar and beverage intake. To better represent long-term diet and reduce measurement error due to within-person variability,
      • Willett W.
      Nutritional epidemiology.
      cumulative updated intake was calculated for adult diet by averaging the repeated measures from all available FFQs up to 2 years before the most recent endoscopy. As an indicator of overall diet during adolescence, we derived prudent and western dietary patterns using principal component analyses as reported previously (Supplementary Table 1).
      • Hu F.B.
      Dietary pattern analysis: a new direction in nutritional epidemiology.
      A western dietary pattern was characterized by high intake of desserts, sweets, snacks, red and processed meat, and refined grains; whereas a prudent pattern was characterized by high intake of vegetables, fruits, better-quality grains, fish, and poultry. For analyses of SSBs, ASBs, and fruit juice, dietary patterns were derived after excluding each beverage variable to avoid collinearity with the primary exposure.

       Outcome Ascertainment

      On each biennial questionnaire, participants were asked whether they underwent a lower bowel endoscopy and the reasons why (screening, family history of CRC, symptoms), and whether CRC or polyps were diagnosed. Self-reported negative colonoscopy was reliable in our cohorts.
      • He X.
      • Hang D.
      • Wu K.
      • et al.
      Long-term risk of colorectal cancer after removal of conventional adenomas and serrated polyps.
      ,
      • Giovannucci E.
      • Ascherio A.
      • Rimm E.B.
      • et al.
      Physical activity, obesity, and risk for colon cancer and adenoma in men.
      In random samples of participants reporting negative colonoscopy (n = 114 in the NHS, 140 in the Health Professionals Follow-Up Study), concordance rate was high between self-reported negative endoscopy and endoscopic record review (97% in the NHS, 100% in the Health Professionals Follow-Up Study). Participants who reported a diagnosis of polyps were asked for permission to access medical and pathologic records. Physicians blinded to participant exposure information reviewed the records to verify the diagnosis and accrue information on polyp size, number, subtype (adenoma, serrated lesion), subsite (proximal, distal, rectal), and histology (tubular, tubulovillous, villous; with or without high-grade dysplasia). We subdivided adenoma into high risk (≥1 cm, any villous histology, high-grade dysplasia, or ≥3 adenomas) and low risk (1–2 tubular adenomas <1 cm in size).
      • Gupta S.
      • Lieberman D.
      • Anderson J.C.
      • et al.
      Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.
      Serrated lesions included hyperplastic polyps, sessile serrated adenoma/polyp, and traditional serrated adenoma,
      • Gill P.
      • Wang L.M.
      • Bailey A.
      • et al.
      Reporting trends of right-sided hyperplastic and sessile serrated polyps in a large teaching hospital over a 4-year period (2009–2012).
      and were subdivided by size (small, <1 cm; large, ≥1 cm) as a predictor for the malignant potential.
      • He X.
      • Hang D.
      • Wu K.
      • et al.
      Long-term risk of colorectal cancer after removal of conventional adenomas and serrated polyps.

       Assessment of Covariates

      From the HS-FFQ and biennial questionnaires during follow-up, we collected and updated information on body mass index (BMI) at age 18 years, adult height, current weight, smoking (adolescent, current), alcohol consumption (age 18–22 years, current), family history of CRC in first-degree relatives, history of type 2 diabetes, menopausal status and menopausal hormone use, and current aspirin use. Information on physical activity during adolescence was obtained in 1997 as described in detail previously.
      • Maruti S.S.
      • Willett W.C.
      • Feskanich D.
      • et al.
      A prospective study of age-specific physical activity and premenopausal breast cancer.
      ,
      • Rezende L.F.M.
      • Lee D.H.
      • Keum N.
      • et al.
      Physical activity during adolescence and risk of colorectal adenoma later in life: results from the Nurses' Health Study II.
      In brief, participants reported average time spent per week on walking and a variety of recreational activities during early life. Each activity was converted to metabolic equivalent of task (MET)-h/wk and then summed to obtain total physical activity.
      • Ainsworth B.E.
      • Haskell W.L.
      • Herrmann S.D.
      • et al.
      2011 Compendium of Physical Activities: a second update of codes and MET values.
      Adolescent physical activity was defined as total physical activity during grades 9 to 12. Physical activity during adulthood was assessed in 1989, 1991, 1997, 2001, 2005, 2009, and 2013, and cumulative updated averages were calculated.

       Statistical Analysis

      Sugar intake was categorized into quintiles using either nutrient density or energy-adjusted intake. SSB and other beverage intake was grouped into 4 categories: <1 serving per week, 1–6 servings per week, 1 serving per day, and ≥2 servings per day. Sugar and SSB intake were also treated as continuous variables. Individuals with missing responses for each exposure variable of interest were excluded from analyses (SSBs, n = 666; ASBs, 840; fruit juice, 56). We generated a new dataset for each questionnaire cycle when participants reported an endoscopy. Thus, participants with multiple endoscopies during follow-up could provide multiple records. Once polyp(s) were diagnosed, the participant was censored. Time-varying variables were updated to 2 years before the most recent endoscopy. To handle individuals with multiple endoscopies and time-varying variables efficiently, the Andersen-Gill data structure was used.
      • Andersen P.K.
      • Gill R.D.
      Cox's regression model for counting processes: a large sample study.
      Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data (SAS PROC GENMOD) where each participant represented a cluster. We constructed 3 multivariable models with adjustment for various potential confounders during both adolescence and adulthood.
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      Model 1 included age, time period of endoscopy, time since most recent endoscopy, number of endoscopies, and reason for endoscopy. Model 2 was additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times per week, history of type 2 diabetes, adult height, BMI (at 18 years and current), smoking (adolescent, current), alcohol consumption (18–22 years, current), and physical activity (adolescent, current). In model 3, to assess whether associations were independent of other dietary factors and overall unhealthy dietary pattern, we further adjusted for adolescent and adult intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding adult variables to adolescent exposure variables.
      Tests for trend were performed by assigning a median value to each category of exposure variables and modeling this value as a continuous variable, using the Wald test to assess statistical significance. Stratified analyses were performed to examine whether associations varied across strata of known CRC risk factors during adolescence (eg, family history of CRC, BMI, physical activity, fruit and vegetable intake). Tests for interaction were performed by including cross-product terms of exposure and stratification variables in the model and using a Wald test. To examine the effects of dietary changes across different life stages, we examined joint associations of adolescent and adult sugar intake with adenoma risk. According to the 2020–2025 DGA,
      U.S. Department of Agriculture and U.S. Department of Health and Human Services
      Dietary guidelines for Americans, 2020–2025.
      the effects of substituting fruits, fruit juice, or dairy for SSBs were estimated by simultaneously including both SSBs and 1 of these food items as continuous variables in models; ORs and 95% CIs were calculated from the differences in coefficients and corresponding variances and covariances.
      • Bernstein A.M.
      • de Koning L.
      • Flint A.J.
      • et al.
      Soda consumption and the risk of stroke in men and women.
      All tests were 2-sided with P < .05 considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

      Results

      Baseline characteristics of the participants are described in Table 1. During adolescence, 12.6% of women had consumed ≥1 serving per day of SSBs (≥2 servings per day, 4.8%), whereas in adulthood, 11.1% consumed ≥1 serving per day (≥2 servings per day, 3.2%). Adolescent SSB intake contributed to 2.6% of daily calories, on average. When stratified by year of birth, younger birth cohorts tended to have higher fructose and SSB intake during adolescence compared with older birth cohorts, largely consistent with the US national data.
      • Cavadini C.
      • Siega-Riz A.M.
      • Popkin B.M.
      US adolescent food intake trends from 1965 to 1996.
      Participants with higher adolescent fructose intake tended to consume less red meat and more fruits and vegetables, but those with higher SSB intake tended to consume more red meat and fewer fruits and vegetables. The correlation between total fructose and SSB intake during adolescence was low to modest (Spearman correlation, r = 0.38; Supplementary Table 2). Adolescent diet was only weakly correlated with adult diet (total fructose, r = 0.26; SSBs, r = 0.25).
      Table 1Baseline Characteristics of Participants by Total Fructose and SSB Intake During Adolescence in the Nurses’ Health Study II
      Means (SD) are presented for continuous variables; percentages for categorical variables. All variables other than age in 1998 and birth year were standardized to the age distribution of the study population.
      Total fructose (% of calorie)SSB intake during adolescence (serving)
      Q1 (<7.9) (n = 6598)Q3 (9.2–10.3) (n = 6682)Q5 (≥11.8) (n = 6639)<1/wk (n = 13,732)1–6/wk (n = 14,545)≥1/d (n = 4163)
      Age at 1998 questionnaire return (y)44.6 (4.4)44.2 (4.6)43.7 (4.5)44.2 (4.5)44.3 (4.5)43.7 (4.5)
      Birth year, %
       1946–194921.821.117.342.047.011.0
       1950–195421.720.218.442.645.412.0
       1955–195918.919.721.242.144.513.4
       1960–196516.920.423.242.542.515.0
      Number of endoscopies during the study period (n)1.2 (0.5)1.2 (0.5)1.2 (0.5)1.2 (0.5)1.2 (0.5)1.2 (0.5)
      Time since most recent endoscopy (y)1.4 (3.8)1.4 (3.8)1.4 (3.8)1.4 (3.8)1.4 (3.8)1.5 (4.0)
      Endoscopy for clinical symptoms or signs
      Includes bleeding in stool, positive test for occult fecal blood, diarrhea or constipation, and abdominal pain.
      , %
      23.422.524.321.623.925.7
      Adult height (inches)64.8 (2.6)64.9 (2.6)64.9 (2.6)65.0 (2.6)64.9 (2.6)64.8 (2.6)
      BMI at age 18 y (kg/m2)21.4 (3.3)21.1 (3.0)21.0 (3.2)21.4 (3.2)20.9 (3.0)21.0 (3.4)
      Current BMI (kg/m2)26.4 (6.0)26.0 (5.8)26.3 (6.1)26.1 (6)26.0 (5.8)26.9 (6.3)
      Smoking before 20 y of age, %21.921.924.019.423.230.3
      Current smoker, %6.55.66.34.75.89.2
      Physical activity at grades 9–12 (MET-h/wk)49.1 (36.1)51.1 (35.1)54.5 (37.6)50.0 (35.6)52.9 (36.5)54.7 (37.9)
      Current physical activity (MET-h/wk)17.5 (21.1)19.0 (22.6)20.5 (26.0)20.4 (24.3)18.4 (22.0)17.4 (24.4)
      Premenopause, %47.048.747.548.648.544.4
      Family history of CRC, %22.422.822.222.622.023.9
      Diabetes, %4.84.34.64.13.95.8
      Current aspirin use (≥2 d/wk), %12.611.313.511.812.713.9
      Food and nutrient intake during adolescence
      Nutrients are energy-adjusted values unless otherwise indicated.
       Unprocessed red meat (g/d)120 (60)109 (48)94 (46)102 (52)110 (50)119 (51)
       Processed red meat (g/d)24 (22)23 (18)20 (17)20 (18)24 (19)26 (21)
       Fruits (serving/d)1.0 (0.6)1.6 (0.8)2.1 (1.5)1.6 (1.1)1.5 (1.0)1.3 (1.0)
       Vegetables (serving/d)2.7 (1.6)3.2 (1.7)3.4 (2.1)3.3 (1.9)3.1 (1.7)2.9 (1.7)
       Total dairy (serving/d)3.0 (1.6)2.9 (1.4)2.3 (1.4)2.8 (1.5)2.8 (1.5)2.7 (1.5)
       SSBs (serving/wk)1.1 (1.5)2.4 (2.6)7.3 (7.6)0.4 (0.4)3.2 (1.7)12.5 (6.7)
       ASBs (serving/wk)2.8 (5.8)2.4 (5.1)2.1 (5.1)3.4 (6.4)1.5 (3.5)1.5 (4.5)
       Fruit juice (serving/wk)2.7 (2.8)5.1 (3.9)6.7 (6.4)4.9 (4.7)5.1 (4.6)4.6 (4.4)
       Total fructose (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      6.7 (1.0)9.7 (0.3)13.6 (1.8)9.0 (2.3)10.1 (2.1)12.6 (2.7)
       Glucose (from simple sugars, % of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      6.7 (1.0)9.5 (0.6)13.2 (1.9)8.7 (2.1)9.8 (2.0)12.5 (2.7)
       Added sugar (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      9.5 (2.3)13.6 (2.6)19.9 (5.4)11.7 (3.6)14.6 (3.6)20.8 (5.4)
       Total sugar (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      18.7 (3.0)23.7 (2.0)30.3 (3.7)22.5 (4.3)24.3 (4.0)28.7 (5.1)
       Calcium (mg/d)1234 (402)1090 (316)919 (272)1157 (373)1065 (320)925 (274)
       Vitamin D (IU/d)410 (212)347 (178)283 (175)379 (211)341 (174)277 (163)
       Folate (μg/d)301 (89)328 (96)334 (116)345 (112)316 (90)281 (80)
       Fiber (g/d)18.6 (4.6)21.1 (4.6)22.3 (6.4)21.9 (5.9)20.4 (4.6)18.7 (4.2)
       Glycemic index54.6 (2.9)54.7 (2.5)55.8 (2.9)54.1 (2.7)55.1 (2.4)57 (2.6)
       Glycemic load148 (22)169 (16)196 (21)165 (25)171 (22)187 (25)
       Alcohol (g/d)0.3 (2.3)0.3 (2.0)0.3 (1.8)0.2 (1.7)0.3 (1.7)0.5 (2.5)
      Current (adult) food and nutrient intake
      Nutrients are energy-adjusted values unless otherwise indicated.
      ,
      Intake from 1999 food frequency questionnaire.
       Unprocessed red meat (g/d)58 (35)56 (33)53 (33)51 (33)58 (33)64 (35)
       Processed red meat (g/d)8 (7)8 (7)7 (7)7 (7)8 (7)9 (8)
       Fruits (serving/d)1.1 (0.7)1.3 (0.8)1.4 (1.0)1.4 (0.8)1.3 (0.8)1.1 (0.8)
       Vegetables (serving/d)3.4 (1.8)3.7 (1.8)3.8 (2.2)3.8 (2.0)3.6 (1.8)3.5 (1.9)
       Total dairy (serving/d)2.1 (1.1)2.2 (1.1)1.9 (1.1)2.1 (1.1)2.1 (1.1)1.9 (1.1)
       SSBs (serving/wk)2.0 (3.4)2.6 (3.9)4.1 (6.0)1.7 (2.8)3.2 (4.2)5.4 (7.2)
       ASBs (serving/wk)6.3 (7.9)5.9 (7.4)6.8 (8.6)6.0 (7.7)5.6 (7.1)8.3 (9.5)
       Fruit juice (serving/wk)3.6 (3.7)4.7 (4.2)5.3 (5.0)4.5 (4.3)4.8 (4.3)4.3 (4.2)
       Total fructose (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      8.4 (2.6)9.4 (2.6)10.6 (3.2)9.1 (2.5)9.7 (2.8)10.2 (3.7)
       Glucose (from simple sugars, % of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      8.2 (2.5)9.2 (2.4)10.3 (3.0)8.8 (2.4)9.4 (2.6)10.0 (3.5)
       Added sugar (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      9.8 (4.4)10.9 (4.5)12.6 (6.0)9.9 (4.0)11.5 (4.9)13.3 (6.8)
       Total sugar (% of calorie)
      From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      21.4 (5.6)23.0 (5.4)24.8 (6.4)22.6 (5.4)23.4 (5.7)24.0 (7.2)
       Calcium (mg/d)1239 (421)1228 (406)1173 (427)1274 (418)1189 (397)1100 (403)
       Vitamin D (IU/d)443 (219)432 (212)409 (222)452 (220)418 (206)381 (209)
       Folate (μg/d)562 (208)573 (204)577 (214)598 (214)562 (200)525 (200)
       Fiber (g/d)19.2 (4.7)20.0 (4.8)20.1 (5.4)20.9 (5.2)19.4 (4.6)18.0 (4.6)
       Alcohol (g/d)4.4 (7.0)4.4 (6.5)4.0 (6.3)4.3 (6.5)4.3 (6.4)4.5 (7.3)
      CRC, colorectal cancer; SSB, sugar-sweetened beverage; ASB, artificially sweetened beverage; IU, international units; MET, metabolic equivalent of tasks; Q, quintile.
      a Means (SD) are presented for continuous variables; percentages for categorical variables. All variables other than age in 1998 and birth year were standardized to the age distribution of the study population.
      b Includes bleeding in stool, positive test for occult fecal blood, diarrhea or constipation, and abdominal pain.
      c Nutrients are energy-adjusted values unless otherwise indicated.
      d From mono- and disaccharide sugars. Total sugar intake was sum of free fructose, free glucose, sucrose, and maltose intake.
      e Intake from 1999 food frequency questionnaire.
      During follow-up, 4744 women were diagnosed with at least 1 colorectal polyp, of whom 2909 had at least 1 adenoma (1548 proximal, 1205 distal, 458 rectal, and 758 high-risk adenomas), and 2355 at least 1 serrated lesion (196 large serrated lesions). The mean age at diagnosis was 52.2 ± 4.3 years, with most cases diagnosed at relatively young ages (76.5% before 55 years). In adenoma cases, the proportions of rectal adenoma tended to be higher among women born after 1960 (born before 1960, 15.2% vs after 1960, 19.6%).

       Sugar and SSB Intake and CRC Precursor Risk

      Independent of adult intake, higher intake of total fructose and SSBs during adolescence was significantly associated with increased risk of total adenoma (Tables 2 and 3). For total fructose intake, positive associations were not significant in models 1 and 2. However, additional adjustment for dietary covariables (especially adolescent fruit, fiber, and calcium intake) substantially strengthened the associations in model 3. In fully adjusted models, the ORs of total adenoma were 1.17 (95% CI, 1.05–1.31; Ptrend = .006) per each increment of 5% of calories from total fructose intake and 1.11 (95% CI, 1.02–1.20; Ptrend = .01) per 1 serving per day of SSB intake. By subsite, higher total fructose intake (per 5% of calories) was associated with increased risk of distal (OR 1.24; 95% CI, 1.05–1.47) and rectal (OR, 1.43; 95% CI, 1.10–1.86) adenoma; higher SSB intake (per 1 serving per day) was associated with increased risk of proximal (OR, 1.13; 95% CI, 1.02–1.26) and rectal (OR, 1.30; 95% CI, 1.08–1.55) adenoma. Neither sugar nor SSB intake during adolescence was associated with risk of total and large serrated lesions (all Ptrend ≥ .35).
      Table 2Odds Ratios and 95% Confidence Intervals of Colorectal Polyps According to Total Fructose Intake During Adolescence in the Nurses’ Health Study II, 1998–2015
      Total fructose intake during adolescence, % of caloriePer 5% of calorie increase
      Q1 (<7.9)Q2 (7.9–<9.2)Q3 (9.2–<10.3)Q4 (10.3–<11.8)Q5 (≥11.8)Ptrend
      Total adenoma
      Ncases/Ncontrols
      Due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      573/9976570/9978595/9954591/9958580/9968
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), and reason for endoscopy (screening/symptoms).
      1 (ref)1.00 (0.89–1.12)1.05 (0.93–1.18)1.05 (0.93–1.18)1.03 (0.92–1.16).441.04 (0.95–1.13)
      Model 2
      In addition, adjusted for family history of CRC (yes/no), menopausal status/menopausal hormone use (premenopausal, postmenopausal with never, past, or current hormone therapy), current aspirin use ≥2 times/wk (yes/no), history of type 2 diabetes (yes/no), adult height (continuous), BMI at age 18 y (<18.5, 18.5–<20, 20–<22.5, 22.5–<25, ≥25 kg/m2), current BMI (<22.5, 22.5–<25, 25–<27.5, 27.5–<30, ≥30 kg/m2), smoking status at 19 y (never, 0≤2.5, >2.5 pack-years), current smoking status (never smoker, past smoker <30 pack-years, past smoker ≥30 pack-years, current smoker <30 pack-years, current smoker ≥30 pack-years), alcohol intake at 18–22 y (<0.1, 0.1–4.9, 5–14.9, ≥15 g/d), current alcohol intake (none, 0.1–4.9, 5–9.9, 10–14.9, ≥15 g/d), physical activity during grades 9–12 (quintile), and current physical activity (<21, 21–<30, 30–<39, 39–<54, ≥54 MET hours/wk).
      1 (ref)1.00 (0.89–1.13)1.06 (0.94–1.20)1.07 (0.95–1.20)1.06 (0.94–1.20).211.06 (0.97–1.16)
      Model 3
      In addition, adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy; quintile), current total red meat intake (quintile), western dietary pattern score during adolescence (quintile), and current total fructose intake.
      1 (ref)1.05 (0.93–1.19)1.14 (1.00–1.30)1.19 (1.04–1.36)1.20 (1.04–1.39).0061.17 (1.05–1.31)
       Proximal adenoma
      Ncases/Ncontrols316/9795306/9807323/9765310/9776293/9809
      Model 31 (ref)1.03 (0.87–1.22)1.15 (0.96–1.36)1.15 (0.96–1.39)1.13 (0.92–1.38).161.12 (0.96–1.30)
       Distal adenoma
      Ncases/Ncontrols239/9795221/9807241/9765251/9776253/9809
      Model 31 (ref)0.97 (0.80–1.18)1.10 (0.90–1.35)1.21 (0.98–1.48)1.25 (1.00–1.56).0141.24 (1.05–1.47)
       Rectal adenoma
      Ncases/Ncontrols77/979597/980784/9765101/977699/9809
      Model 31 (ref)1.39 (1.01–1.89)1.24 (0.90–1.73)1.61 (1.15–2.25)1.62 (1.14–2.31).0081.43 (1.10–1.86)
      Total serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols479/9951442/9993486/9945486/9934462/9983
      Model 31 (ref)0.93 (0.80–1.07)1.03 (0.89–1.20)1.06 (0.91–1.23)1.01 (0.86–1.19).491.04 (0.92–1.18)
       Small serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols405/9951374/9993420/9945430/9934386/9983
      Model 31 (ref)0.93 (0.80–1.08)1.06 (0.91–1.24)1.12 (0.96–1.32)1.01 (0.85–1.21).411.06 (0.93–1.21)
       Large serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols46/995141/999340/994529/993440/9983
      Model 31 (ref)0.88 (0.57–1.37)0.85 (0.54–1.35)0.60 (0.36–1.00)0.86 (0.54–1.37).350.83 (0.56–1.22)
      Subtype of polyp
       Adenoma only
      Ncases/Ncontrols472/9598488/9618482/9581469/9594478/9608
      Model 31 (ref)1.10 (0.96–1.26)1.13 (0.98–1.30)1.15 (0.99–1.34)1.20 (1.03–1.41).0271.15 (1.02–1.30)
       Serrated lesion only
      Ncases/Ncontrols378/9598360/9618373/9581364/9594360/9608
      Model 31 (ref)0.96 (0.82–1.12)1.00 (0.85–1.17)0.99 (0.84–1.17)0.99 (0.83–1.18).991.00 (0.87–1.15)
       Both adenoma and serrated lesion
      Ncases/Ncontrols101/959882/9618113/9581122/9594102/9608
      Model 31 (ref)0.84 (0.62–1.14)1.20 (0.89–1.61)1.36 (1.01–1.85)1.20 (0.85–1.67).061.28 (0.99–1.65)
      N, number of endoscopies; Q, quintile
      a Due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      b Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), and reason for endoscopy (screening/symptoms).
      c In addition, adjusted for family history of CRC (yes/no), menopausal status/menopausal hormone use (premenopausal, postmenopausal with never, past, or current hormone therapy), current aspirin use ≥2 times/wk (yes/no), history of type 2 diabetes (yes/no), adult height (continuous), BMI at age 18 y (<18.5, 18.5–<20, 20–<22.5, 22.5–<25, ≥25 kg/m2), current BMI (<22.5, 22.5–<25, 25–<27.5, 27.5–<30, ≥30 kg/m2), smoking status at 19 y (never, 0≤2.5, >2.5 pack-years), current smoking status (never smoker, past smoker <30 pack-years, past smoker ≥30 pack-years, current smoker <30 pack-years, current smoker ≥30 pack-years), alcohol intake at 18–22 y (<0.1, 0.1–4.9, 5–14.9, ≥15 g/d), current alcohol intake (none, 0.1–4.9, 5–9.9, 10–14.9, ≥15 g/d), physical activity during grades 9–12 (quintile), and current physical activity (<21, 21–<30, 30–<39, 39–<54, ≥54 MET hours/wk).
      d In addition, adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy; quintile), current total red meat intake (quintile), western dietary pattern score during adolescence (quintile), and current total fructose intake.
      e Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Table 3Odds Ratios and 95% Confidence Intervals of Colorectal Polyps According to SSB Intake During Adolescence in the Nurses’ Health Study II, 1998–2015
      SSB intake during adolescence, servingsPer 1 serving/day increase
      <1/wk1–6/wk1/d≥2/dPtrend
      Total adenoma
      Ncases/Ncontrols
      Due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      1224/205871201/22103267/3834161/2300
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies, time since most recent endoscopy, reason for endoscopy (screening/symptoms).
      1 (ref)0.91 (0.84–0.99)1.19 (1.04–1.37)1.19 (1.01–1.42).0071.10 (1.03–1.17)
      Model 2
      In addition, adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height, BMI (age 18 y, current), smoking status (adolescent, current), alcohol consumption (age 18–22 y, current), physical activity (adolescent, current).
      1 (ref)0.92 (0.84–1.00)1.18 (1.03–1.36)1.18 (0.99–1.40).0121.09 (1.02–1.17)
      Model 3
      In addition, adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current SSB intake.
      1 (ref)0.92 (0.84–1.00)1.20 (1.03–1.39)1.21 (1.00–1.48).0101.11 (1.02–1.20)
       Proximal adenoma
      Ncases/Ncontrols655/20214630/21732147/375786/2257
      Model 31 (ref)0.91 (0.81–1.03)1.25 (1.03–1.53)1.27 (0.96–1.66).0231.13 (1.02–1.26)
       Distal adenoma
      Ncases/Ncontrols503/20214508/21732110/375764/2257
      Model 31 (ref)0.94 (0.82–1.07)1.18 (0.94–1.48)1.14 (0.84–1.55).211.08 (0.96–1.22)
       Rectal adenoma
      Ncases/Ncontrols188/20214174/2173250/375733/2257
      Model 31 (ref)0.88 (0.70–1.09)1.50 (1.06–2.12)1.68 (1.07–2.63).0051.30 (1.08–1.55)
      Total serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols917/206671095/21921179/3881121/2322
      Model 31 (ref)1.11 (1.01–1.23)1.01 (0.84–1.20)1.14 (0.91–1.43).351.04 (0.96–1.14)
       Small serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols780/20667940/21921158/3881100/2322
      Model 31 (ref)1.14 (1.02–1.26)1.07 (0.88–1.29)1.14 (0.89–1.45).321.05 (0.96–1.15)
       Large serrated lesion
      Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols84/2066790/2192111/38819/2322
      Model 31 (ref)0.96 (0.70–1.32)0.63 (0.32–1.22)0.88 (0.41–1.87).480.89 (0.64–1.23)
      Subtype of polyp
       Adenoma only
      Ncases/Ncontrols1010/19884985/21224222/3700126/2214
      Model 31 (ref)0.94 (0.85–1.03)1.24 (1.05–1.46)1.19 (0.95–1.48).0251.10 (1.01–1.20)
       Serrated lesion only
      Ncases/Ncontrols703/19884879/21224134/370086/2214
      Model 31 (ref)1.18 (1.05–1.31)1.02 (0.84–1.25)1.10 (0.85–1.43).551.03 (0.93–1.14)
       Both adenoma and serrated lesion
      Ncases/Ncontrols214/19884216/2122445/370035/2214
      Model 31 (ref)0.89 (0.73–1.09)1.02 (0.73–1.44)1.32 (0.87–2.01).181.13 (0.95–1.34)
      N, number of endoscopies
      a Due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      b Adjusted for age, time period of endoscopy, number of endoscopies, time since most recent endoscopy, reason for endoscopy (screening/symptoms).
      c In addition, adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height, BMI (age 18 y, current), smoking status (adolescent, current), alcohol consumption (age 18–22 y, current), physical activity (adolescent, current).
      d In addition, adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current SSB intake.
      e Includes hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma; small, <1 cm; large, ≥1 cm.
      Results for glucose (from simple sugars), added sugar, and total sugar were similar to the results for total fructose, but effect sizes were slightly smaller than total fructose (Supplementary Table 3). Neither ASB nor fruit juice intake was associated with risk of adenoma (Supplementary Table 4). Contrary to adolescent intake, sugar intake during adulthood was not associated with adenoma risk. After adjustment for adolescent intake, the multivariable ORs for total adenoma were 0.96 (95% CI, 0.87–1.06) for adult intake of total fructose (per 5% of calories) and 0.94 (95% CI, 0.86–1.03) for SSBs (per 1 serving per day).

       Sugar and SSB Intake and Risk of High-Risk Adenoma

      Higher intake of total fructose during adolescence was positively associated with high-risk adenoma (Table 4). The multivariable ORs of high-risk adenoma were 1.30 (95% CI, 1.06–1.60; Ptrend = .012) per 5% of calories from total fructose intake. By subsite, higher fructose intake (per 5% of calories) was borderline significantly associated with increased risk of distal (OR, 1.33; 95% CI, 1.00–1.78; Ptrend = .052) and rectal (OR, 1.47; 95% CI, 0.99–2.19; Ptrend = .055) high-risk adenoma. Higher adolescent SSB intake (per 1 serving per day) was significantly associated with rectal high-risk adenoma with the OR of 1.34 (95% CI, 1.01–1.79; Ptrend = .044).
      Table 4Multivariable Odds Ratios and 95% Confidence Intervals of Low- and High-Risk Colorectal Adenoma According to Total Fructose and SSB Intake During Adolescence in the Nurses’ Health Study II, 1998–2015
      Total fructose intake during adolescence, % of caloriePer 5% of calorie increase
      Q1 (<7.9)Q2 (7.9–<9.2)Q3 (9.2–<10.3)Q4 (10.3–<11.8)Q5 (≥11.8)Ptrend
      Low-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols
      N, number of endoscopies; due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      346/9795316/9807342/9765307/9776317/9809
      Multivariable
      Adjusted for age, time period of endoscopy, number of endoscopies, time since most recent endoscopy, reason for endoscopy, family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height, BMI (age 18 y, current), smoking status (adolescent, current), alcohol consumption (age 18–22 y, current), physical activity (adolescent, current), adolescent and current dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
      1 (ref)0.95 (0.81–1.12)1.07 (0.90–1.26)1.00 (0.83–1.20)1.07 (0.88–1.30).411.07 (0.92–1.24)
      High-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases131152149168158
      Multivariable1 (ref)1.24 (0.97–1.59)1.25 (0.97–1.62)1.49 (1.15–1.94)1.40 (1.06–1.86).0121.30 (1.06–1.60)
       Proximal
      Ncases8272757879
      Multivariable1 (ref)0.99 (0.71–1.38)1.08 (0.77–1.52)1.23 (0.85–1.77)1.30 (0.89–1.89).111.28 (0.95–1.72)
       Distal
      Ncases6271828589
      Multivariable1 (ref)1.17 (0.82–1.68)1.37 (0.95–1.98)1.46 (1.02–2.10)1.44 (0.97–2.14).0521.33 (1.00–1.78)
       Rectal
      Ncases2639284935
      Multivariable1 (ref)1.65 (0.99–2.77)1.23 (0.70–2.15)2.35 (1.38–4.02)1.65 (0.93–2.92).0551.47 (0.99–2.19)
      SSB intake during adolescence, servingsPer 1 serving/day increase
      <1/wk1–6/wk1/d≥2/dPtrend
      Low-risk adenoma
      Ncases/Ncontrols676/20214687/21732151/375789/2257
      Multivariable1 (ref)0.96 (0.86–1.08)1.24 (1.02–1.51)1.26 (0.98–1.64).0221.13 (1.02–1.25)
      High-risk adenoma
      Ncases3223057342
      Multivariable1 (ref)0.85 (0.72–1.01)1.19 (0.90–1.56)1.08 (0.74–1.59).411.07 (0.92–1.24)
       Proximal
      Ncases1711493921
      Multivariable1 (ref)0.80 (0.63–1.03)1.23 (0.84–1.80)1.05 (0.60–1.83).581.06 (0.85–1.33)
       Distal
      Ncases1571633922
      Multivariable1 (ref)0.92 (0.72–1.16)1.22 (0.84–1.78)1.08 (0.64–1.82).531.07 (0.87–1.31)
       Rectal
      Ncases77612113
      Multivariable1 (ref)0.77 (0.54–1.11)1.62 (0.96–2.72)1.74 (0.85–3.57).0441.34 (1.01–1.79)
      a Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      b N, number of endoscopies; due to multiple endoscopies during follow-up per each participant, N is larger than number of participants.
      c Adjusted for age, time period of endoscopy, number of endoscopies, time since most recent endoscopy, reason for endoscopy, family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height, BMI (age 18 y, current), smoking status (adolescent, current), alcohol consumption (age 18–22 y, current), physical activity (adolescent, current), adolescent and current dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
      Similar (but somewhat weaker) results were found for glucose (from simple sugars), added sugar, and total sugar (Supplementary Table 3). Sugar and SSB intake during adulthood was not associated with high-risk adenoma with multivariable ORs of 0.97 (95% CI, 0.80–1.17) for total fructose (per 5% of calories) and 0.99 (95% CI, 0.84–1.16) for SSBs (per 1 serving per day) after adjustment for adolescent intake.

       Risk of Adenoma by Age at Diagnosis

      We stratified adenoma cases into 3 groups by age at diagnosis: <50, 50 to 54, and ≥55 years (Supplementary Table 5). Per each increment of 5% of calories, total fructose intake during adolescence was positively associated with risk of total adenoma diagnosed <50 years (Ptrend = .07) and 50 to 54 years (Ptrend = .02), but no association was found for adenoma diagnosed at ≥55 years (Ptrend = .42). In particular, adolescent total fructose intake was significantly associated with increased risk of rectal adenoma diagnosed at <50 and 50 to 54 years (Ptrend ≤ .04) and high-risk adenoma diagnosed at <50 years (Ptrend = .004). For adolescent SSB intake, similar, albeit weaker, positive associations were observed with rectal adenoma diagnosed at <50 and 50 to 54 years (per 1 serving per day, Ptrend ≤ .07).

       Sensitivity Analysis

      Overall, sensitivity analysis results were consistent with the principal findings (Supplementary Table 6, Supplementary Table 7, Supplementary Table 8). In brief, similar results were obtained after further adjustment for ASB and fruit juice intake or prudent dietary pattern, use of energy-adjusted sugar intake (instead of nutrient densities), and restricting analyses to individuals who underwent colonoscopy. When the omitted responses to SSB items (n = 666) on the HS-FFQ were set to zero or estimated intake from regression,
      • Michels K.B.
      • Willett W.C.
      Self-administered semiquantitative food frequency questionnaires: patterns, predictors, and interpretation of omitted items.
      associations were essentially unchanged (data not presented). We conducted further analyses for serrated lesions in the proximal colon (n = 802) and large (≥1 cm) proximal serrated lesions (n = 145), and found no significant association (Supplementary Table 9).
      After additional adjustment for glycemic index and glycemic load as potential mediators, positive associations were substantially attenuated, especially after adjustment for glycemic load: per each increment of 5% of calories from total fructose, ORs were 1.08 (95% CI, 0.94–1.25) for total and 1.21 (95% CI, 0.94–1.55) for high-risk adenoma (Supplementary Table 6).

       Stratified Analysis

      Associations of fructose and SSB intake with adenoma risk did not differ appreciably by family history of CRC, birth year, adolescent BMI, physical activity, smoking, or alcohol consumption (all Pinteraction ≥ .15; Figure 1, Supplementary Table 10). Positive associations between sugar intake and adenoma risk were significantly stronger among women with low fruit intake (<1.3 servings per day) during adolescence than women with high intake (≥1.3 servings per day). Among those with low fruit intake, ORs of total adenoma were 1.51 (95% CI, 1.26–1.82; Pinteraction < .001) for total fructose (highest vs lowest quintile) and 1.34 (95% CI, 1.12–1.60; Pinteraction = .028) for SSBs (≥1 serving/day vs <1 serving/week). Similar differential associations were observed after stratification by vegetable and fiber intake and prudent dietary pattern. In contrast, positive associations with adenoma risk did not differ appreciably by fruit juice intake (Pinteraction ≥ .75). By joint categories of fruit (high/low) and fruit juice (high/low) intake, positive associations were strongest in the “low fruit/high fruit juice” subgroup, with significant differences across subgroups (Pinteraction ≤ .017; Figure 1). Stratified analysis results for high-risk adenoma were similar to those for total adenoma (Supplementary Table 11).
      Figure thumbnail gr1
      Figure 1Risk of total adenoma according to (A) total fructose and (B) SSB intake during adolescence by lifestyle and dietary factors in the Nurses’ Health Study II, 1998–2015. Data were adjusted for age, time period of endoscopy, number of endoscopies, time since most recent endoscopy, reason for endoscopy, family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height, BMI (age 18 years, current), smoking status (adolescent, current), alcohol consumption (age 18–22 years, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum. (A) Highest vs lowest (referent) quintile. (B) ≥1 serving/d vs <1 serving/wk (referent). aHigh: highest tertile (≥59 MET-h/wk); low: 2 lower tertiles (<59 MET-h/wk). bCutoff: median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).

       Joint Analysis of Adolescent and Adult Diet

      Compared with women with low fructose or SSB intake during both adolescence and adulthood, women with high intake during adolescence had increased risk of total, rectal, and high-risk adenoma (Supplementary Table 12, Supplementary Figure 1). Associations did not differ significantly between the “high adolescent/low adult intake” and “high adolescent/high adult intake” groups. However, these results should be cautiously interpreted given higher added sugar and calorie intake during adolescence and differences in nutritional/caloric requirements between adolescence and adulthood.

       Substitution Analysis

      The 2020–2025 DGA recommends 2 cup-equivalents of fruits (whole fruits and 100% fruit juice) at the 2000-calorie level and 2 to 3 cup-equivalents of dairy per day for children and adolescents.
      U.S. Department of Agriculture and U.S. Department of Health and Human Services
      Dietary guidelines for Americans, 2020–2025.
      Substituting 1 serving per day of fruit juice for 1 serving per day of SSBs during adolescence was not associated with lower risk of adenoma (Supplementary Table 13). In contrast, replacement with 2 servings per day of fruits for 2 servings per day of SSBs was marginally associated with reduced risk of proximal (OR, 0.75; 95% CI, 0.54–1.05) and rectal (OR, 0.61; 95% CI, 0.35–1.07) adenoma. Substituting 2 servings per day of dairy products for 2 servings per day of SSBs was significantly associated with lower risk of rectal adenoma (OR, 0.53; 95% CI, 0.30–0.94).

      Discussion

      In this large cohort of young women, high intake of simple sugars, especially fructose, and SSBs during adolescence was significantly associated with increased risk of colorectal adenoma, particularly rectal adenoma. Results were similar, albeit slightly weaker, for glucose, added sugar, and total sugar. Neither sugar nor SSB intake was associated with risk of serrated lesions. Thus, high sugar intake during adolescence may be etiologically more important for CRC arising from the conventional adenoma-carcinoma sequence, which accounts for approximately 85% of CRC,
      • Strum W.B.
      Colorectal adenomas.
      rather than the serrated neoplasia pathway.
      To our knowledge, no previous study has investigated the association of adolescent sugar intake with risk of CRC precursors. Previous studies on adult sugar and SSB intake in relation to CRC risk have generally found null associations, including 2 comprehensive pooled analyses of prospective studies as well as a recent large cohort study.
      • Zhang X.
      • Albanes D.
      • Beeson W.L.
      • et al.
      Risk of colon cancer and coffee, tea, and sugar-sweetened soft drink intake: pooled analysis of prospective cohort studies.
      ,
      Imperial College London Continuous Update Project
      World Cancer Research Fund International Systematic Literature Review: The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer.
      ,
      • Pacheco L.S.
      • Anderson C.A.M.
      • Lacey Jr., J.V.
      • et al.
      Sugar-sweetened beverages and colorectal cancer risk in the California Teachers Study.
      In 2018, the World Cancer Research Fund/American Institute for Cancer Research reported that evidence was limited for sugars and foods containing sugars with regard to CRC risk.
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      ,
      Imperial College London Continuous Update Project
      World Cancer Research Fund International Systematic Literature Review: The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer.
      However, this conclusion was based on intake during adulthood, mostly capturing mid-to-late adulthood cases. Consistent with previous studies, we observed that adult sugar and SSB intake was not associated with adenoma risk. One possible explanation for the differential associations between adolescent vs adult sugar intake is that adolescence may be a critical developmental period of enhanced susceptibility to the adverse effects of high sugar intake. During adolescence, accompanied by growth and accelerated cell proliferation, distinctive hormonal and metabolic changes occur, including physiological (obesity-unrelated) hyperinsulinemia, decreased insulin sensitivity, and elevated IGF1 levels (up to 4-fold higher than in adulthood).
      • Hannon T.S.
      • Janosky J.
      • Arslanian S.A.
      Longitudinal study of physiologic insulin resistance and metabolic changes of puberty.
      Therefore, adolescents may be particularly susceptible to high sugar intake that can further decrease insulin sensitivity.
      Several biological mechanisms may explain our findings. First, hyperinsulinemia and insulin resistance may play important roles. The high amount of liquid sugar in SSBs can induce rapid spikes in blood glucose and insulin levels, which over time lead to insulin resistance and elevated free IGF1 levels.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      The insulin/IGF1 system can promote carcinogenesis by activating intracellular signaling pathways related to altered gene expression, stimulating cell proliferation, differentiation, and angiogenesis, and inhibiting apoptosis.
      • Keum N.
      • Giovannucci E.
      Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
      ,
      • Vigneri P.G.
      • Tirrò E.
      • Pennisi M.S.
      • et al.
      The Insulin/IGF System in colorectal cancer development and resistance to therapy.
      We found that additional adjustment for dietary glycemic load substantially attenuated positive associations of high sugar intake, supporting this hypothesis.
      Second, hyperglycemia may exacerbate chronic inflammation that has been implicated in CRC pathogenesis.
      • Wu J.
      • Cai Q.
      • Li H.
      • et al.
      Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men's Health Study.
      Previous studies have reported that SSB intake was significantly associated with increased circulating inflammatory cytokines and biomarkers (eg, C-reactive protein, interleukin-6, tumor necrosis factor receptors).
      • Yu Z.
      • Ley S.H.
      • Sun Q.
      • et al.
      Cross-sectional association between sugar-sweetened beverage intake and cardiometabolic biomarkers in US women.
      ,
      • de Koning L.
      • Malik V.S.
      • Kellogg M.D.
      • et al.
      Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men.
      Third, the distinctive metabolism of fructose, a major ingredient of SSBs, can exert additional adverse effects. Unlike glucose, fructose is metabolized predominantly in the liver after absorption in the small intestine.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      When fructose intake chronically exceeds the metabolic capacity of the liver, fructose triggers hepatic de novo lipogenesis, promoting visceral and ectopic fat accumulation, glucose intolerance, and insulin resistance.
      • Bray G.A.
      • Nielsen S.J.
      • Popkin B.M.
      Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
      In a recent animal study, fructose was metabolized into glucose in murine small intestine as well, and intestinal fructose-to-glucose conversion was not suppressed by insulin, suggestive of a novel unregulated pathway.
      • Jang C.
      • Hui S.
      • Lu W.
      • et al.
      The small intestine converts dietary fructose into glucose and organic acids.
      Furthermore, fructose may affect carcinogenesis by directly acting on colorectal cells or interacting with the gut microbiome. Although fructose is readily absorbed in the small intestine, high doses or rapid flux of fructose could saturate small intestine clearance capacity, with excess fructose reaching the colon.
      • Jang C.
      • Hui S.
      • Lu W.
      • et al.
      The small intestine converts dietary fructose into glucose and organic acids.
      ,
      • Zhao S.
      • Jang C.
      • Liu J.
      • et al.
      Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
      An 8-week oral administration of high-fructose corn syrup in mice enhanced colorectal tumor cell growth, even at a moderate dose, in the absence of obesity and metabolic syndrome, suggesting direct effects of fructose on tumor cell metabolism.
      • Goncalves M.D.
      • Lu C.
      • Tutnauer J.
      • et al.
      High-fructose corn syrup enhances intestinal tumor growth in mice.
      Moreover, sugars may change the gut microbiome composition,
      • Do M.H.
      • Lee E.
      • Oh M.J.
      • et al.
      High-glucose or -fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change.
      ,
      • Di Rienzi S.C.
      • Britton R.A.
      Adaptation of the gut microbiota to modern dietary sugars and sweeteners.
      which could affect CRC development through modulation of gut immune and metabolic responses and epigenetic alterations.
      • Wong S.H.
      • Yu J.
      Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.
      ,
      • Song M.
      • Chan A.T.
      • Sun J.
      Influence of the gut microbiome, diet, and environment on risk of colorectal cancer.
      In stratified analyses, positive associations of high sugar intake were significantly stronger among women with low fruit, vegetable, or fiber intake during adolescence than those with high intake. However, fruit juice intake did not offset the adverse effects of high sugar intake, and substituting fruit juice for SSBs showed no benefits. These results may be explained as follows: although fruits and some vegetables contain naturally occurring sugars,
      • Johnson R.K.
      • Appel L.J.
      • Brands M.
      • et al.
      Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.
      many beneficial micronutrients and potential anti-tumorigenic agents (eg, fiber, folate, vitamins) may offset or dilute the adverse effects of sugars.
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      Moreover, whole fruits and fruit juice have different intestinal fructose release rates.
      • Jang C.
      • Hui S.
      • Lu W.
      • et al.
      The small intestine converts dietary fructose into glucose and organic acids.
      Fructose in whole fruits is slowly digested due to the fiber content and the need to disrupt cell structure, facilitating gradual and complete intestinal clearance.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      In contrast, rapid flux of liquid fructose from fruit juice may exceed small intestine uptake capacity, resulting in fructose overflow to the liver and colon.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      ,
      • Jang C.
      • Hui S.
      • Lu W.
      • et al.
      The small intestine converts dietary fructose into glucose and organic acids.
      ,
      • Zhao S.
      • Jang C.
      • Liu J.
      • et al.
      Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
      We also found stronger associations among women with unhealthy (low prudent and high western) dietary patterns during adolescence than those with healthy patterns. Thus, excessive sugar intake may promote colorectal carcinogenesis particularly when combined with overall unhealthy dietary patterns by further exacerbating underlying chronic insulin resistance.
      • Giovannucci E.
      A framework to understand diet, physical activity, body weight, and cancer risk.
      If confirmed, our findings may have substantial public health implications for the prevention of CRC. The rising incidence of sporadic CRC among younger adults has been primarily driven by a disproportional increase in distal and rectal cancers.
      • Keum N.
      • Giovannucci E.
      Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
      ,
      • Siegel R.L.
      • Miller K.D.
      • Goding Sauer A.
      • et al.
      Colorectal cancer statistics, 2020.
      In our results, positive associations were stronger for distally located adenoma, especially rectal adenoma. Simple sugar intake during adolescence was more strongly associated with adenoma diagnosed at <55 years, further supporting the link between early-life diet and earlier initiation of colorectal carcinogenesis. In recent decades, the global SSB consumption among youths has markedly increased.
      • Rosinger A.
      • Herrick K.
      • Gahche J.
      • et al.
      Sugar-sweetened beverage consumption among U.S. youth, 2011–2014.
      • Malik V.S.
      • Hu F.B.
      Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
      • Yang L.
      • Bovet P.
      • Liu Y.
      • et al.
      Consumption of carbonated soft drinks among young adolescents aged 12 to 15 years in 53 low- and middle-income countries.
      In the United States, 65.4% of adolescents consumed SSBs on a given day in 2013–2014,
      • Bleich S.N.
      • Vercammen K.A.
      • Koma J.W.
      • et al.
      Trends in beverage consumption among children and adults, 2003–2014.
      and 72% of male and 76% of female adolescents exceeded the DGA limit of added sugar intake (<10% of total calorie) in 2013–2016.
      U.S. Department of Agriculture and U.S. Department of Health and Human Services
      Dietary guidelines for Americans, 2020–2025.
      Therefore, if applied to the current general population, the impact of high sugar intake may be even larger than observed in our results.
      This study has several strengths. To our knowledge, this is the first prospective study investigating the role of high sugar intake during adolescence in risk of colorectal polyps. Dietary data were collected before endoscopic procedures and polyp diagnoses, thus minimizing the potential of recall bias. The large sample size of 33,106 women and 4744 polyp cases enabled assessment by subtypes and subsites, and stratified analyses with sufficient power. Diet and lifestyle information was validated and obtained throughout different life stages, enabling us to examine both independent and joint associations of adolescent and adult diet. We comprehensively updated information on and adjusted for most of the established CRC risk factors during both adolescence and adulthood. In rigorous sensitivity analyses, the principal results were robust.
      Potential limitations of this study need to be considered. First, substantial measurement error is likely in adult recall of adolescent diet. However, the HS-FFQ showed reasonable reproducibility and validity,
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      ,
      • Maruti S.S.
      • Feskanich D.
      • Rockett H.R.
      • et al.
      Validation of adolescent diet recalled by adults.
      supporting the ability to rank individuals adequately. Recalled adolescent diet was only weakly correlated with current diet.
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      ,
      • Maruti S.S.
      • Feskanich D.
      • Rockett H.R.
      • et al.
      Validation of adolescent diet recalled by adults.
      Although recall time period varied between participants (16–35 years later), a previous study showed that adult age was not related to the reproducibility of recalled diet during high school, a distinct time of life.
      • Frazier A.L.
      • Willett W.C.
      • Colditz G.A.
      Reproducibility of recall of adolescent diet: Nurses' Health Study (United States).
      In addition, given the prospective design, any measurement error in exposure assessment should be nondifferential, which generally attenuates risk estimates toward the null association.
      • Maruti S.S.
      • Feskanich D.
      • Colditz G.A.
      • et al.
      Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
      Second, residual and unmeasured confounding could exist. High sugar intake could be a marker for generally unhealthy diet and lifestyle that might track throughout life. However, we controlled for numerous dietary and lifestyle factors as well as overall dietary patterns during both adolescence and adulthood. Third, we did not have sufficient information to distinguish hyperplastic polyps from sessile serrated adenoma/polyp and traditional serrated adenoma because diagnostic criteria for serrated lesions have changed over time. All endoscopies in this study were performed when standardized diagnostic criteria for serrated lesions were not routinely applied by pathologists.
      • Gill P.
      • Wang L.M.
      • Bailey A.
      • et al.
      Reporting trends of right-sided hyperplastic and sessile serrated polyps in a large teaching hospital over a 4-year period (2009–2012).
      Finally, the study population consisted of predominantly white female nurses, and thus results may not be generalizable to other populations. However, secular trends in CRC incidence are similar by sex, and incidence rates in those younger than 45 years are comparable between men and women in the United States,
      American Cancer Society
      Colorectal Cancer Facts & Figures 2020–2022.
      reflecting shared main drivers. In addition, exposure-CRC associations in our cohorts have been highly consistent with findings in diverse populations,
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective.
      ,
      • Rezende L.F.M.
      • Lee D.H.
      • Keum N.
      • et al.
      Physical activity during adolescence and risk of colorectal adenoma later in life: results from the Nurses' Health Study II.
      ,
      • Zhang X.
      • Keum N.
      • Wu K.
      • et al.
      Calcium intake and colorectal cancer risk: results from the nurses' health study and health professionals follow-up study.
      suggesting a common underlying biology.
      In conclusion, high intake of simple sugars and SSBs during adolescence was significantly associated with increased risk of total and high-risk adenoma, especially rectal adenoma. Given the profound increase in added sugar and SSB intake during the past several decades, our findings may partly explain the current upward trends in early-onset CRC rates. Further prospective studies using valid information on early-life diet in other populations are warranted to confirm our findings.

      Acknowledgments

      The authors thank the Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School. The authors thank the participants and staff of the Nurses’ Health Study II for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for analyses and interpretation of these data. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Return of the mailed questionnaire was considered to imply informed consent.

      CRediT Authorship Contributions

      Hee-Kyung Joh, MD, MPH, PhD (Conceptualization: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Project administration: Equal; Validation:
      Supporting; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead)
      Dong Hoon Lee, PhD (Methodology: Supporting; Validation: Lead)
      Jinhee Hur, PhD (Writing – review & editing: Equal)
      Katharina Nimptsch, PhD (Formal analysis: Supporting; Writing – review & editing: Equal). Yoosoo Chang, MD, PhD (Writing – review & editing: Equal)
      Hyojee Joung, MPH, PhD (Writing – review & editing: Equal)
      Xuehong Zhang, MD, ScD (Writing – review & editing: Equal)
      Leandro F. M. Rezende, ScD (Writing – review & editing: Equal)
      Jung Eun Lee, ScD (Writing – review & editing: Equal)
      Kimmie Ng, MD, MPH (Writing – review & editing: Equal). Yuan Chen, ScD (Writing – review & editing: Equal)
      Fred K. Tabung, PhD, MSPH (Methodology: Supporting; Validation: Supporting; Writing – review & editing: Equal)
      Jeffrey A. Meyerhardt, MD, MPH (Writing – review & editing: Equal)
      Andrew T. Chan, MD, MPH (Writing – review & editing: Equal)
      Tobias Pischon, MD, PhD (Writing – review & editing: Equal)
      Mingyang Song, MD, ScD (Writing – review & editing: Equal)
      Charles S. Fuchs, MD, MPH (Writing – review & editing: Equal)
      Walter C. Willett, MD, DrPH (Data curation: Lead; Methodology: Supporting; Project administration: Supporting; Resources: Supporting; Software: Supporting; Supervision: Supporting; Validation: Equal; Writing – review & editing: Equal)
      Yin Cao, ScD, MPH (Writing – review & editing: Equal)
      Shuji Ogino, MD, MS, PhD (Funding acquisition: Supporting; Writing – review & editing: Equal)
      Edward Giovannucci, MD, ScD (Conceptualization: Equal; Data curation: Supporting; Funding acquisition: Supporting; Investigation: Equal; Methodology: Equal; Project administration: Supporting; Resources: Supporting; Supervision: Equal; Writing – review & editing: Equal)
      Kana Wu, MD, PhD (Conceptualization: Lead; Data curation: Lead; Funding acquisition: Lead; Investigation: Equal; Methodology: Equal; Project administration: Equal; Resources: Equal; Software: Supporting; Supervision: Equal; Writing – original draft: Equal; Writing – review & editing: Lead).

      Supplementary Material

      Supplementary Table 1Factor Loadings for Western and Prudent Dietary Patterns From the HS-FFQ in the Nurses’ Health Study II
      Food groupAll foodsAll foods except sodaAll foods except fruit juice
      PrudentWesternPrudentWesternPrudentWestern
      Other vegetables0.770.770.78
      Leafy green vegetables0.720.720.72
      Cruciferous vegetables0.680.680.68
      Yellow vegetables0.660.660.66
      Fruit0.650.650.64
      Tomatoes0.570.570.58
      Legumes0.520.160.510.180.530.17
      Salad dressing0.440.230.440.440.23
      Garlic0.430.430.240.44
      Fruit juice0.410.40
      Excluded variable in principal component analyses.
      Excluded variable in principal component analyses.
      Better quality grains0.390.380.38
      Fish0.370.170.370.180.370.18
      Poultry0.300.180.300.180.300.18
      Potato salad0.270.270.270.270.280.27
      Low-fat dairy0.260.260.25
      Organ meat0.190.190.20
      Tea
      Diet soda
      Coffee
      Desserts and sweets0.620.620.62
      Condiments0.150.620.640.150.62
      Snack foods0.180.570.180.570.180.58
      Processed meat0.560.570.56
      Fries0.540.510.54
      Refined grains0.530.550.53
      Red meat0.520.530.52
      Mayonnaise0.190.440.170.450.190.44
      Nuts/peanut butter0.260.420.240.440.250.43
      High-fat dairy0.410.430.42
      Soda−0.160.40
      Excluded variable in principal component analyses.
      Excluded variable in principal component analyses.
      −0.160.40
      Pizza0.360.340.36
      Potato (mashed, boiled)0.340.360.34
      Eggs0.320.340.31
      Margarine0.250.270.25
      Butter0.230.230.23
      Cream soup (Chowder)0.160.180.190.150.18
      Iced tea0.180.160.17
      Cereals
      NOTE. Factor loadings are equivalent to Person correlation coefficients. Factor loadings <0.15 are not displayed for simplicity.
      a Excluded variable in principal component analyses.
      Supplementary Table 2Age-Adjusted Spearman Correlation Coefficients of Sugar and Sweetened Beverage Intake During Adolescence and Adulthood
      Correlation between adolescent intake of sweetened beverages and sugars
      Adolescent intake
      SSBsASBsFruit juiceTotal fructose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Total glucose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Added sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Total sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Glycemic load
      Adolescent intake
       SSBs1−0.180.0040.380.430.540.350.25
       ASBs1−0.02−0.06−0.07−0.07−0.12−0.08
       Fruit juice10.270.20−0.0020.280.20
       Total fructose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      10.930.720.840.67
       Total glucose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      10.810.820.67
       Added sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      10.650.48
       Total sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      10.59
      Correlation between adolescent and adult intake
      Current (adult) intake
      SSBsASBsFruit juiceTotal fructose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Total glucose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Added sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Total sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Adolescent intake
       SSBs0.25
       ASBs0.32
       Fruit juice0.38
       Total fructose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      0.26
       Total glucose
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      0.25
       Added sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      0.25
       Total sugar
      From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      0.25
      ASBs, artificially sweetened beverages.
      a From mono- and disaccharide sugars. Total sugar intake was defined as sum of free fructose, free glucose, sucrose, and maltose intake.
      Supplementary Table 3ORs and 95% CIs of Colorectal Polyp According to Glucose, Added Sugar, and Total Sugar Intake During Adolescence
      Glucose intake during adolescence, % of caloriePer 5% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols564/9984598/9951574/9974593/9957580/9968
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)1.09 (0.96–1.22)1.06 (0.94–1.19)1.10 (0.98–1.24)1.09 (0.96–1.24).0231.14 (1.02–1.27)
      Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)1.08 (0.96–1.22)1.05 (0.93–1.19)1.10 (0.97–1.24)1.09 (0.96–1.24).0231.14 (1.02–1.27)
      Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current sugar intake (quintiles) in model 2.
      1 (ref)1.12 (0.99–1.26)1.11 (0.98–1.26)1.18 (1.03–1.34)1.18 (1.03–1.36).0231.14 (1.02–1.27)
       Proximal adenoma
      Ncases/Ncontrols311/9806313/9771323/9793314/9780287/9802
      Model 31 (ref)1.07 (0.91–1.26)1.16 (0.97–1.38)1.15 (0.96–1.39)1.09 (0.90–1.32).3471.08 (0.92–1.26)
       Distal adenoma
      Ncases/Ncontrols233/9806241/9771226/9793248/9780257/9802
      Model 31 (ref)1.09 (0.90–1.32)1.06 (0.86–1.30)1.20 (0.98–1.47)1.28 (1.03–1.58).0201.23 (1.03–1.46)
       Rectal adenoma
      Ncases/Ncontrols79/9806100/977184/979391/9780104/9802
      Model 31 (ref)1.35 (0.99–1.85)1.18 (0.85–1.63)1.32 (0.94–1.84)1.55 (1.09–2.19).0301.35 (1.03–1.78)
       Low-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols337/9806341/9771324/9793312/9780314/9802
      Model 31 (ref)1.06 (0.90–1.24)1.03 (0.87–1.22)1.02 (0.85–1.22)1.06 (0.88–1.28).6581.03 (0.89–1.20)
       High-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols131/9806153/9771147/9793166/9780161/9802
      Model 31 (ref)1.23 (0.97–1.58)1.23 (0.95–1.59)1.42 (1.10–1.84)1.37 (1.04–1.80).0211.28 (1.04–1.58)
      Total serrated lesions
      Included hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma.
      Ncases/Ncontrols457/9980469/9965471/9952495/9928463/9981
      Model 31 (ref)1.03 (0.89–1.19)1.06 (0.91–1.22)1.13 (0.97–1.31)1.06 (0.90–1.24).3371.06 (0.94–1.21)
       Small serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols382/9980406/9965408/9952426/9928393/9981
      Model 31 (ref)1.07 (0.92–1.25)1.10 (0.94–1.29)1.18 (1.00–1.38)1.09 (0.92–1.30).2351.09 (0.95–1.24)
       Large serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols49/998035/996537/995242/992833/9981
      Model 31 (ref)0.69 (0.44–1.09)0.74 (0.46–1.18)0.81 (0.52–1.28)0.64 (0.40–1.01).1420.75 (0.52–1.10)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols470/9621509/9571453/9624481/9574476/9609
      Model 31 (ref)1.15 (1.01–1.32)1.06 (0.92–1.22)1.15 (1.00–1.34)1.17 (1.00–1.36).0881.11 (0.98–1.26)
       Serrated lesion only
      Ncases/Ncontrols363/9621380/9571350/9624383/9574359/9609
      Model 31 (ref)1.06 (0.91–1.23)0.97 (0.83–1.15)1.09 (0.92–1.29)1.02 (0.86–1.22).7701.02 (0.89–1.17)
       Both adenoma and serrated lesion
      Ncases/Ncontrols94/962189/9571121/9624112/9574104/9609
      Model 31 (ref)0.97 (0.72–1.31)1.36 (1.02–1.83)1.32 (0.97–1.79)1.27 (0.92–1.77).0611.27 (0.99–1.64)
      Added sugar intake during adolescence, % of caloriePer 5% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols568/9979580/9970550/9999579/9970632/9916
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)1.02 (0.91–1.15)0.98 (0.87–1.11)1.04 (0.92–1.18)1.15 (1.02–1.30).0251.07 (1.01–1.13)
      Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)1.02 (0.90–1.15)0.96 (0.85–1.09)1.02 (0.90–1.15)1.13 (1.00–1.28).0251.07 (1.01–1.13)
      Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current sugar intake (quintiles) in model 2.
      1 (ref)1.01 (0.90–1.15)0.97 (0.85–1.10)1.04 (0.91–1.19)1.16 (1.01–1.33).0251.07 (1.01–1.13)
       Proximal adenoma
      Ncases/Ncontrols306/9794309/9801301/9821307/9801325/9735
      Model 31 (ref)0.99 (0.84–1.17)0.98 (0.83–1.17)1.03 (0.86–1.23)1.10 (0.91–1.33).2501.05 (0.97–1.13)
       Distal adenoma
      Ncases/Ncontrols241/9794235/9801221/9821238/9801270/9735
      Model 31 (ref)0.97 (0.81–1.18)0.92 (0.75–1.12)1.02 (0.83–1.25)1.20 (0.97–1.48).0601.09 (1.00–1.19)
       Rectal adenoma
      Ncases/Ncontrols84/979487/980185/982193/9801109/9735
      Model 31 (ref)1.06 (0.77–1.45)1.06 (0.76–1.46)1.18 (0.85–1.65)1.35 (0.96–1.91).0621.14 (0.99–1.32)
       Low-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols333/9794319/9801306/9821330/9801340/9735
      Model 31 (ref)0.93 (0.79–1.10)0.90 (0.76–1.07)1.00 (0.84–1.18)1.06 (0.88–1.27).3461.04 (0.96–1.12)
       High-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols138/9794156/9801138/9821153/9801173/9735
      Model 31 (ref)1.11 (0.88–1.41)0.97 (0.76–1.25)1.11 (0.86–1.44)1.22 (0.93–1.59).1631.08 (0.97–1.21)
      Total serrated lesions
      Included hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma.
      Ncases/Ncontrols444/10000448/9982454/9971524/9899485/9954
      Model 31 (ref)0.99 (0.86–1.14)1.00 (0.87–1.16)1.17 (1.01–1.35)1.08 (0.92–1.27).1101.05 (0.99–1.12)
       Small serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols373/10000387/9982394/9971450/9899411/9954
      Model 31 (ref)1.02 (0.87–1.19)1.05 (0.90–1.22)1.21 (1.04–1.42)1.11 (0.94–1.32).0791.06 (0.99–1.14)
       Large serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols41/1000039/998233/997143/989940/9954
      Model 31 (ref)0.90 (0.57–1.42)0.75 (0.46–1.23)0.94 (0.60–1.48)0.87 (0.53–1.41).7020.96 (0.78–1.18)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols473/9630481/9621449/9646473/9552513/9550
      Model 31 (ref)1.02 (0.89–1.17)0.96 (0.83–1.11)1.04 (0.90–1.21)1.14 (0.98–1.33).0671.06 (1.00–1.13)
       Serrated lesion only
      Ncases/Ncontrols349/9630349/9621353/9646418/9552366/9550
      Model 31 (ref)0.98 (0.84–1.15)0.99 (0.85–1.17)1.19 (1.01–1.40)1.05 (0.88–1.25).2351.04 (0.97–1.12)
       Both adenoma and serrated lesion
      Ncases/Ncontrols95/963099/9621101/9646106/9552119/9550
      Model 31 (ref)0.98 (0.73–1.31)1.01 (0.75–1.36)1.07 (0.79–1.44)1.25 (0.92–1.71).1091.11 (0.98–1.27)
      Total sugar intake during adolescence, % of caloriePer 10% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols557/9990563/9987620/9928568/9982601/9947
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)1.03 (0.91–1.16)1.16 (1.02–1.30)1.07 (0.95–1.21)1.14 (1.01–1.29).0051.18 (1.05–1.31)
      Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)1.03 (0.91–1.16)1.16 (1.03–1.31)1.08 (0.95–1.22)1.16 (1.02–1.31).0051.18 (1.05–1.31)
      Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current sugar intake (quintiles) in model 2.
      1 (ref)1.02 (0.90–1.16)1.17 (1.03–1.33)1.10 (0.96–1.25)1.20 (1.05–1.38).0051.18 (1.05–1.31)
       Proximal adenoma
      Ncases/Ncontrols301/9824312/9787323/9760298/9817314/9764
      Model 31 (ref)1.05 (0.89–1.24)1.13 (0.95–1.34)1.07 (0.89–1.28)1.17 (0.97–1.41).1051.14 (0.97–1.32)
       Distal adenoma
      Ncases/Ncontrols229/9824224/9787241/9760252/9817259/9764
      Model 31 (ref)1.00 (0.82–1.22)1.13 (0.93–1.37)1.21 (0.99–1.48)1.29 (1.05–1.59).0051.29 (1.08–1.53)
       Rectal adenoma
      Ncases/Ncontrols81/982481/9787112/976083/9817101/9764
      Model 31 (ref)1.05 (0.77–1.44)1.57 (1.16–2.14)1.19 (0.86–1.64)1.53 (1.11–2.12).0091.42 (1.09–1.85)
       Low-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols315/9824338/9787327/9760319/9817329/9764
      Model 31 (ref)1.08 (0.91–1.27)1.07 (0.90–1.27)1.07 (0.90–1.27)1.15 (0.96–1.38).1731.11 (0.95–1.29)
       High-risk adenoma
      Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Ncases/Ncontrols136/9824144/9787171/9760149/9817158/9764
      Model 31 (ref)1.12 (0.87–1.43)1.38 (1.08–1.77)1.24 (0.96–1.60)1.34 (1.03–1.74).0261.27 (1.03–1.57)
      Total serrated lesions
      Included hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma.
      Ncases/Ncontrols462/9986447/9981505/9919469/9956472/9964
      Model 31 (ref)0.98 (0.85–1.12)1.17 (1.02–1.35)1.10 (0.95–1.27)1.12 (0.97–1.31).0521.13 (1.00–1.28)
       Small serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols391/9986381/9981433/9919410/9956400/9964
      Model 31 (ref)0.98 (0.84–1.14)1.19 (1.02–1.39)1.15 (0.98–1.34)1.14 (0.97–1.34).0401.15 (1.01–1.31)
       Large serrated lesion
      Small, <1 cm; large, ≥1 cm.
      Ncases/Ncontrols43/998645/998144/991928/995636/9964
      Model 31 (ref)1.07 (0.69–1.67)1.09 (0.69–1.74)0.68 (0.41–1.13)0.91 (0.57–1.45).3180.82 (0.56–1.21)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols461/9624465/9638514/9529457/9624492/9584
      Model 31 (ref)1.02 (0.89–1.17)1.18 (1.02–1.35)1.06 (0.91–1.22)1.18 (1.02–1.37).0281.15 (1.02–1.30)
       Serrated lesion only
      Ncases/Ncontrols366/9624349/9638399/9529358/9624363/9584
      Model 31 (ref)0.96 (0.82–1.12)1.17 (1.00–1.36)1.05 (0.89–1.23)1.08 (0.92–1.28).2211.09 (0.95–1.25)
       Both adenoma and serrated lesion
      Ncases/Ncontrols96/962498/9638106/9529111/9624109/9584
      Model 31 (ref)1.02 (0.76–1.36)1.21 (0.90–1.62)1.30 (0.96–1.76)1.33 (0.97–1.81).0301.33 (1.03–1.72)
      Q, quintile; N, number of endoscopies.
      a Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      b Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      c Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current sugar intake (quintiles) in model 2.
      d Low-risk: small (<1 cm) 1–2 tubular adenomas; high-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      e Included hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma.
      f Small, <1 cm; large, ≥1 cm.
      Supplementary Table 4ORs and 95% CIs of Colorectal Polyp According to Artificially Sweetened Beverage (ASB) and Fruit Juice Intake During Adolescence
      ASB intake during adolescence, servingsPer 1 serving/d increase
      <1/week1–6/week1/day≥2/dayPtrend
      Total adenoma
      Ncases/Ncontrols1956/32720582/10361159/2860151/2613
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)0.95 (0.86–1.05)0.95 (0.80–1.12)0.97 (0.81–1.16).5960.98 (0.92–1.05)
      Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)0.93 (0.84–1.03)0.91 (0.77–1.09)0.94 (0.78–1.12).3270.97 (0.90–1.04)
      Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current beverage intake in model 2.
      1 (ref)0.94 (0.84–1.04)0.92 (0.77–1.10)0.93 (0.78–1.12).3370.97 (0.90–1.04)
       Proximal adenoma
      Ncases/Ncontrols1023/32111323/1019187/281680/2572
      Model 31 (ref)1.00 (0.87–1.15)0.97 (0.77–1.23)0.96 (0.74–1.23).7080.98 (0.89–1.08)
       Distal adenoma
      Ncases/Ncontrols813/32111244/1019159/281665/2572
      Model 31 (ref)0.92 (0.79–1.08)0.79 (0.60–1.05)0.92 (0.70–1.21).3170.94 (0.85–1.06)
       Rectal adenoma
      Ncases/Ncontrols318/3211180/1019132/281619/2572
      Model 31 (ref)0.79 (0.60–1.04)1.09 (0.74–1.62)0.66 (0.40–1.09).1600.88 (0.73–1.05)
       Low-risk adenoma
      Ncases/Ncontrols1097/32111338/1019182/281675/2572
      Model 31 (ref)0.95 (0.83–1.09)0.83 (0.65–1.05)0.82 (0.64–1.06).0670.91 (0.83–1.01)
       High-risk adenoma
      Ncases/Ncontrols495/32111152/1019153/281646/2572
      Model 31 (ref)1.02 (0.83–1.25)1.28 (0.94–1.73)1.16 (0.83–1.61).2151.08 (0.96–1.22)
      Total serrated lesions
      Ncases/Ncontrols1535/32756504/10303130/2859122/2622
      Model 31 (ref)1.03 (0.92–1.16)0.95 (0.78–1.15)0.97 (0.79–1.20).7190.99 (0.91–1.07)
       Small serrated lesion
      Ncases/Ncontrols1310/32756436/10303112/2859105/2622
      Model 31 (ref)1.05 (0.93–1.19)0.96 (0.78–1.19)0.99 (0.79–1.23).8730.99 (0.91–1.08)
       Large serrated lesion
      Ncases/Ncontrols128/3275645/103038/28599/2622
      Model 31 (ref)1.07 (0.73–1.55)0.65 (0.31–1.33)0.82 (0.40–1.66).4080.89 (0.68–1.17)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols1623/31518470/9969132/2757118/2524
      Model 31 (ref)0.92 (0.82–1.03)0.93 (0.77–1.13)0.88 (0.72–1.08).1770.95 (0.87–1.03)
       Serrated lesion only
      Ncases/Ncontrols1202/31518392/9969103/275789/2524
      Model 31 (ref)1.01 (0.89–1.15)0.96 (0.77–1.19)0.91 (0.72–1.16).4420.97 (0.88–1.06)
       Both adenoma and serrated lesion
      Ncases/Ncontrols333/31518112/996927/275733/2524
      Model 31 (ref)1.04 (0.83–1.31)0.87 (0.57–1.31)1.16 (0.79–1.72).6151.04 (0.89–1.22)
      Fruit juice intake during adolescence, servingsPer 1 serving/d increase
      <1/week1–6/week1/day≥2/dayPtrend
      Total adenoma
      Ncases/Ncontrols555/93081431/24656805/13706114/2080
      Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)1.00 (0.90–1.11)1.06 (0.94–1.20)1.05 (0.85–1.32).3191.04 (0.96–1.13)
      Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)1.01 (0.91–1.12)1.08 (0.95–1.22)1.06 (0.85–1.33).2561.05 (0.97–1.13)
      Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current beverage intake in model 2.
      1 (ref)1.00 (0.90–1.12)1.08 (0.94–1.24)1.10 (0.87–1.40).1941.06 (0.97–1.16)
       Proximal adenoma
      Ncases/Ncontrols276/9151795/24216418/1346355/2038
      Model 31 (ref)1.13 (0.97–1.32)1.14 (0.94–1.39)1.11 (0.79–1.55).4991.04 (0.92–1.18)
       Distal adenoma
      Ncases/Ncontrols229/9151575/24216345/1346354/2038
      Model 31 (ref)0.98 (0.83–1.16)1.11 (0.89–1.37)1.24 (0.87–1.77).1201.11 (0.97–1.28)
       Rectal adenoma
      Ncases/Ncontrols110/9151215/24216119/1346314/2038
      Model 31 (ref)0.77 (0.60–0.99)0.89 (0.65–1.21)0.73 (0.40–1.35).5560.94 (0.75–1.17)
       Low-risk adenoma
      Ncases/Ncontrols326/9151801/24216438/1346360/2038
      Model 31 (ref)0.94 (0.81–1.09)0.98 (0.82–1.18)0.98 (0.71–1.36).9001.01 (0.89–1.14)
       High-risk adenoma
      Ncases/Ncontrols138/9151373/24216215/1346331/2038
      Model 31 (ref)1.07 (0.86–1.33)1.21 (0.92–1.58)1.25 (0.79–1.96).1791.12 (0.95–1.32)
      Total serrated lesions
      Ncases/Ncontrols493/92561150/24649620/1374187/2079
      Model 31 (ref)0.84 (0.75–0.95)0.84 (0.71–0.98)0.82 (0.62–1.07).1500.93 (0.83–1.03)
       Small serrated lesion
      Ncases/Ncontrols425/9256977/24649539/1374170/2079
      Model 31 (ref)0.83 (0.73–0.94)0.85 (0.72–1.00)0.78 (0.58–1.04).1590.92 (0.82–1.03)
       Large serrated lesion
      Ncases/Ncontrols42/9256100/2464945/137418/2079
      Model 31 (ref)0.95 (0.64–1.40)0.82 (0.49–1.37)1.06 (0.44–2.52).8250.96 (0.66–1.39)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols455/89151178/23759659/1323293/2014
      Model 31 (ref)1.01 (0.89–1.13)1.08 (0.93–1.26)1.09 (0.84–1.41).2931.05 (0.96–1.16)
       Serrated lesion only
      Ncases/Ncontrols393/8915897/23759474/1323266/2014
      Model 31 (ref)0.82 (0.72–0.94)0.79 (0.67–0.94)0.74 (0.55–1.00).0470.89 (0.79–1.00)
       Both adenoma and serrated lesion
      Ncases/Ncontrols100/8915253/23759146/1323221/2014
      Model 31 (ref)0.93 (0.72–1.20)1.02 (0.73–1.41)1.09 (0.63–1.88).5961.06 (0.86–1.30)
      a Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      b Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      c Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and corresponding current beverage intake in model 2.
      Supplementary Table 5Multivariable ORs and 95% CIs of Colorectal Adenoma by Age at Diagnosis According to Total Fructose and SSB Intake During Adolescence
      Age at diagnosisTotal fructoseSSBs
      NcasesPer 5% of calorie increasePtrendNcasesPer 1 serving/day increasePtrend
      Total adenoma
       <50 y4581.28 (0.98–1.68).0744471.08 (0.79–1.48).63
       50–54 y13341.22 (1.03–1.44).02110321.13 (0.94–1.35).19
       ≥55 y11171.08 (0.90–1.29).4211041.16 (0.96–1.41).13
      Proximal adenoma
       <50 y2081.25 (0.84–1.87).282030.98 (0.60–1.62).95
       50–54 y6861.15 (0.91–1.45).246681.21 (0.94–1.55).13
       ≥55 y6541.05 (0.83–1.33).666471.19 (0.93–1.53).17
      Distal adenoma
       <50 y2091.25 (0.84–1.85).272041.22 (0.78–1.90).39
       50–54 y5771.27 (0.99–1.64).0645691.01 (0.78–1.31).95
       ≥55 y4191.18 (0.89–1.57).244121.20 (0.87–1.65).26
      Rectal adenoma
       <50 y822.23 (1.27–3.90).005801.84 (0.96–3.55).067
       50–54 y2221.50 (1.02–2.21).0402131.50 (0.97–2.33).070
       ≥55 y1541.06 (0.68–1.65).801521.12 (0.69–1.82).66
      High-risk adenoma
      High-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
       <50 y1371.93 (1.24–3.00).0041301.46 (0.86–2.48).16
       50–54 y3431.12 (0.81–1.53).503360.96 (0.66–1.39).81
       ≥55 y2781.29 (0.91–1.82).152761.11 (0.77–1.60).59
      NOTE. Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
      a High-risk: large (≥1 cm), any villous histology, high-grade dysplasia, or more than 3 adenomas.
      Supplementary Table 6ORs and 95% CIs of Colorectal Adenoma According to Total Fructose and SSB Intake During Adolescence After Additional Adjustment for Dietary Factors
      Total fructose intake during adolescence, % of caloriePer 5% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Model 3
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
       Total adenoma1 (ref)1.05 (0.93–1.19)1.14 (1.00–1.30)1.19 (1.04–1.36)1.20 (1.04–1.39).0061.17 (1.05–1.31)
       Distal adenoma1 (ref)0.97 (0.80–1.18)1.10 (0.90–1.35)1.21 (0.98–1.48)1.25 (1.00–1.56).0141.24 (1.05–1.47)
       Rectal adenoma1 (ref)1.39 (1.01–1.89)1.24 (0.90–1.73)1.61 (1.15–2.25)1.62 (1.14–2.31).0081.43 (1.10–1.86)
       High-risk adenoma1 (ref)1.24 (0.97–1.59)1.25 (0.97–1.62)1.49 (1.15–1.94)1.40 (1.06–1.86).0121.30 (1.06–1.60)
      Model 3 + red meat intake
      As quintiles.
       Total adenoma1 (ref)1.05 (0.93–1.19)1.14 (1.00–1.30)1.19 (1.03–1.36)1.20 (1.03–1.39).0091.17 (1.04–1.31)
       Distal adenoma1 (ref)0.96 (0.79–1.17)1.09 (0.89–1.34)1.19 (0.96–1.47)1.22 (0.96–1.54).0351.22 (1.01–1.46)
       Rectal adenoma1 (ref)1.40 (1.02–1.91)1.26 (0.91–1.75)1.64 (1.17–2.30)1.67 (1.17–2.38).0051.46 (1.12–1.91)
       High-risk adenoma1 (ref)1.26 (0.98–1.61)1.27 (0.98–1.65)1.52 (1.17–1.99)1.45 (1.09–1.94).0081.34 (1.08–1.66)
      Model 3 + prudent dietary pattern
      As quintiles.
      (in place of western dietary pattern)
       Total adenoma1 (ref)1.05 (0.93–1.19)1.14 (1.00–1.29)1.18 (1.03–1.35)1.19 (1.03–1.37).0071.16 (1.04–1.30)
       Distal adenoma1 (ref)0.97 (0.80–1.18)1.10 (0.90–1.35)1.20 (0.98–1.47)1.24 (0.99–1.54).0161.23 (1.04–1.46)
       Rectal adenoma1 (ref)1.38 (1.01–1.88)1.22 (0.88–1.69)1.56 (1.12–2.18)1.56 (1.10–2.20).0141.38 (1.07–1.79)
       High-risk adenoma1 (ref)1.24 (0.97–1.59)1.25 (0.97–1.62)1.49 (1.15–1.93)1.39 (1.06–1.83).0131.30 (1.06–1.59)
      Model 3 + prudent dietary pattern
      As quintiles.
      (in addition to western dietary pattern)
       Total adenoma1 (ref)1.05 (0.93–1.19)1.14 (1.00–1.30)1.19 (1.04–1.36)1.20 (1.04–1.39).0061.17 (1.05–1.31)
       Distal adenoma1 (ref)0.97 (0.80–1.18)1.10 (0.90–1.35)1.20 (0.98–1.48)1.24 (1.00–1.55).0151.24 (1.04–1.47)
       Rectal adenoma1 (ref)1.39 (1.02–1.90)1.25 (0.90–1.73)1.61 (1.15–2.25)1.62 (1.14–2.31).0081.43 (1.10–1.86)
       High-risk adenoma1 (ref)1.25 (0.97–1.60)1.27 (0.98–1.64)1.52 (1.17–1.98)1.43 (1.08–1.89).0081.33 (1.08–1.63)
      Model 3 + SSB intake
      As categories (<1 serving/wk, 1–6 serving/wk, 1 serving/d, ≥2 serving/d).
       Total adenoma1 (ref)1.07 (0.94–1.22)1.17 (1.02–1.34)1.22 (1.06–1.41)1.18 (1.00–1.40).0221.16 (1.02–1.32)
       Distal adenoma1 (ref)0.99 (0.81–1.21)1.14 (0.93–1.41)1.27 (1.02–1.58)1.29 (1.00–1.67).0151.28 (1.05–1.56)
       Rectal adenoma1 (ref)1.41 (1.02–1.96)1.32 (0.94–1.86)1.66 (1.16–2.37)1.51 (1.00–2.29).0491.36 (1.00–1.85)
       High-risk adenoma1 (ref)1.27 (0.98–1.63)1.34 (1.03–1.75)1.60 (1.21–2.10)1.51 (1.09–2.10).0071.40 (1.10–1.79)
      Model 3 + fruit juice intake
      As categories (<1 serving/wk, 1–6 serving/wk, 1 serving/d, ≥2 serving/d).
       Total adenoma1 (ref)1.06 (0.93–1.20)1.14 (1.00–1.30)1.18 (1.03–1.36)1.19 (1.03–1.38).0091.16 (1.04–1.30)
       Distal adenoma1 (ref)0.97 (0.80–1.18)1.10 (0.89–1.35)1.19 (0.96–1.47)1.22 (0.97–1.53).0301.22 (1.02–1.45)
       Rectal adenoma1 (ref)1.42 (1.04–1.95)1.29 (0.93–1.79)1.67 (1.19–2.34)1.68 (1.18–2.39).0051.46 (1.12–1.90)
       High-risk adenoma1 (ref)1.24 (0.96–1.59)1.24 (0.95–1.61)1.46 (1.12–1.91)1.37 (1.03–1.82).0251.27 (1.03–1.58)
      Model 3 + glycemic index
      As quintiles.
       Total adenoma1 (ref)1.05 (0.93–1.20)1.14 (1.00–1.30)1.19 (1.04–1.36)1.19 (1.03–1.37).0091.16 (1.04–1.29)
       Distal adenoma1 (ref)0.97 (0.80–1.18)1.10 (0.90–1.35)1.21 (0.98–1.48)1.24 (0.99–1.55).0171.23 (1.04–1.47)
       Rectal adenoma1 (ref)1.39 (1.02–1.90)1.24 (0.90–1.72)1.61 (1.15–2.25)1.61 (1.13–2.28).0081.42 (1.10–1.84)
       High-risk adenoma1 (ref)1.24 (0.97–1.59)1.25 (0.97–1.62)1.49 (1.15–1.94)1.39 (1.05–1.84).0141.30 (1.06–1.60)
      Model 3 + glycemic load
      As quintiles.
       Total adenoma1 (ref)1.02 (0.89–1.16)1.08 (0.94–1.24)1.10 (0.95–1.28)1.09 (0.92–1.30).2531.08 (0.94–1.25)
       Distal adenoma1 (ref)0.94 (0.77–1.15)1.05 (0.84–1.30)1.13 (0.89–1.43)1.17 (0.89–1.54).1401.18 (0.95–1.46)
       Rectal adenoma1 (ref)1.40 (1.02–1.93)1.24 (0.88–1.75)1.56 (1.09–2.24)1.43 (0.95–2.17).1221.29 (0.94–1.77)
       High-risk adenoma1 (ref)1.20 (0.93–1.56)1.19 (0.91–1.57)1.40 (1.04–1.86)1.27 (0.91–1.76).1431.21 (0.94–1.55)
      SSB intake during adolescence, servingsPer 1 serving/d increase
      <1/week1–6/week1/day≥2/dayPtrend
      Model 3
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
       Total adenoma1 (ref)0.92 (0.84–1.00)1.20 (1.03–1.39)1.21 (1.00–1.48).0101.11 (1.02–1.20)
       Proximal adenoma1 (ref)0.91 (0.81–1.03)1.25 (1.03–1.53)1.27 (0.96–1.66).0231.13 (1.02–1.26)
       Rectal adenoma1 (ref)0.88 (0.70–1.09)1.50 (1.06–2.12)1.68 (1.07–2.63).0051.30 (1.08–1.55)
       High-risk adenoma1 (ref)0.85 (0.72–1.01)1.19 (0.90–1.56)1.08 (0.74–1.59).4031.07 (0.92–1.24)
      Model 3 + red meat intake
      As quintiles.
       Total adenoma1 (ref)0.92 (0.84–1.00)1.19 (1.03–1.39)1.21 (0.99–1.47).0121.11 (1.02–1.19)
       Proximal adenoma1 (ref)0.91 (0.81–1.03)1.25 (1.03–1.53)1.27 (0.96–1.66).0231.13 (1.02–1.26)
       Rectal adenoma1 (ref)0.88 (0.70–1.09)1.50 (1.07–2.12)1.68 (1.07–2.64).0041.30 (1.08–1.56)
       High-risk adenoma1 (ref)0.85 (0.72–1.02)1.19 (0.90–1.57)1.09 (0.74–1.60).3831.07 (0.92–1.25)
      Model 3 + prudent dietary pattern
      As quintiles.
      (in place of western dietary pattern)
       Total adenoma1 (ref)0.91 (0.84–1.00)1.18 (1.02–1.37)1.19 (0.98–1.44).0181.10 (1.02–1.18)
       Proximal adenoma1 (ref)0.91 (0.80–1.02)1.24 (1.02–1.52)1.25 (0.96–1.63).0251.13 (1.02–1.25)
       Rectal adenoma1 (ref)0.86 (0.69–1.07)1.44 (1.02–2.03)1.58 (1.02–2.45).0091.27 (1.06–1.51)
       High-risk adenoma1 (ref)0.85 (0.72–1.01)1.18 (0.90–1.56)1.08 (0.74–1.57).4001.07 (0.92–1.24)
      Model 3 + prudent dietary pattern
      As quintiles.
      (in addition to western dietary pattern)
       Total adenoma1 (ref)0.91 (0.84–1.00)1.18 (1.01–1.37)1.18 (0.97–1.44).0231.10 (1.01–1.18)
       Proximal adenoma1 (ref)0.90 (0.80–1.02)1.23 (1.01–1.51)1.23 (0.94–1.62).0381.12 (1.01–1.25)
       Rectal adenoma1 (ref)0.86 (0.68–1.07)1.44 (1.02–2.03)1.58 (1.00–2.47).0111.26 (1.06–1.51)
       High-risk adenoma1 (ref)0.85 (0.72–1.01)1.19 (0.90–1.57)1.09 (0.74–1.59).3861.07 (0.92–1.25)
      Model 3 + ASB intake + fruit juice intake
      Fructose from SSBs: as quintiles except for rectal adenoma (<0.6, 0.65-<3.0, ≥3.0% of calories).
       Total adenoma1 (ref)0.91 (0.83–0.99)1.20 (1.03–1.39)1.21 (0.99–1.48).0131.11 (1.02–1.20)
       Proximal adenoma1 (ref)0.90 (0.79–1.01)1.27 (1.03–1.55)1.24 (0.94–1.64).0341.13 (1.01–1.26)
       Rectal adenoma1 (ref)0.89 (0.71–1.12)1.50 (1.06–2.14)1.80 (1.15–2.83).0021.33 (1.11–1.59)
       High-risk adenoma1 (ref)0.87 (0.72–1.03)1.23 (0.93–1.63)1.20 (0.81–1.76).1731.11 (0.95–1.30)
      Model 3 + glycemic index
      As quintiles.
       Total adenoma1 (ref)0.91 (0.83–0.99)1.15 (0.99–1.34)1.14 (0.93–1.39).0701.08 (0.99–1.17)
       Proximal adenoma1 (ref)0.89 (0.79–1.01)1.20 (0.98–1.47)1.16 (0.87–1.53).1201.09 (0.98–1.22)
       Rectal adenoma1 (ref)0.87 (0.69–1.08)1.46 (1.04–2.07)1.61 (1.02–2.56).0091.28 (1.06–1.54)
       High-risk adenoma1 (ref)0.85 (0.71–1.01)1.16 (0.88–1.54)1.02 (0.69–1.52).5841.05 (0.89–1.22)
      Model 3 + glycemic load
      As quintiles.
       Total adenoma1 (ref)0.90 (0.82–0.98)1.13 (0.97–1.32)1.11 (0.90–1.37).1181.07 (0.98–1.16)
       Proximal adenoma1 (ref)0.89 (0.79–1.01)1.20 (0.98–1.47)1.19 (0.89–1.59).0881.11 (0.99–1.24)
       Rectal adenoma1 (ref)0.85 (0.68–1.07)1.41 (0.99–2.00)1.45 (0.89–2.34).0391.22 (1.01–1.48)
       High-risk adenoma1 (ref)0.82 (0.69–0.97)1.09 (0.82–1.45)0.93 (0.62–1.40).9611.00 (0.85–1.18)
      Model 3 + fructose from SSBs
      Fructose from SSBs: as quintiles except for rectal adenoma (<0.6, 0.65-<3.0, ≥3.0% of calories).
       Total adenoma1 (ref)0.93 (0.81–1.07)1.13 (0.90–1.41)1.05 (0.77–1.42).6591.03 (0.91–1.16)
       Proximal adenoma1 (ref)0.90 (0.75–1.09)1.07 (0.79–1.45)0.91 (0.60–1.38).7270.97 (0.82–1.15)
       Rectal adenoma1 (ref)0.80 (0.55–1.16)1.51 (0.85–2.66)1.71 (0.90–3.26).0141.33 (1.06–1.66)
       High-risk adenoma1 (ref)0.91 (0.73–1.13)1.08 (0.76–1.54)0.87 (0.53–1.41).6000.95 (0.78–1.15)
      a Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
      b As quintiles.
      c Fructose from SSBs: as quintiles except for rectal adenoma (<0.6, 0.65-<3.0, ≥3.0% of calories).
      d As categories (<1 serving/wk, 1–6 serving/wk, 1 serving/d, ≥2 serving/d).
      Supplementary Table 7Multivariable ORs and 95% CIs of Colorectal Polyp According to Calorie-Adjusted Intake of Sugars During Adolescence
      Total fructose intake during adolescence (g/d)Per 35 g/d increase
      Corresponds to 5% of calorie intake in study participants.
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols584/9965544/10005623/9924588/9962570/9978
      Multivariable
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current sugar intake.
      1 (ref)0.98 (0.86–1.11)1.18 (1.04–1.34)1.15 (1.01–1.32)1.17 (1.01–1.35).0081.16 (1.04–1.30)
       Proximal adenoma
      Ncases/Ncontrols319/9784308/9839332/9724302/9779287/9826
      Multivariable1 (ref)1.02 (0.86–1.20)1.16 (0.98–1.38)1.10 (0.91–1.32)1.09 (0.89–1.32).3401.08 (0.92–1.26)
       Distal adenoma
      Ncases/Ncontrols242/9784212/9839246/9724254/9779251/9826
      Multivariable1 (ref)0.91 (0.75–1.11)1.12 (0.92–1.36)1.20 (0.97–1.47)1.23 (0.99–1.53).0111.25 (1.05–1.49)
       Rectal adenoma
      Ncases/Ncontrols83/978478/9839102/972493/9779102/9826
      Multivariable1 (ref)1.01 (0.73–1.40)1.41 (1.03–1.93)1.34 (0.96–1.88)1.56 (1.11–2.18).0041.47 (1.13–1.91)
       Low-risk adenoma
      Ncases/Ncontrols351/9784309/9839341/9724324/9779303/9826
      Multivariable1 (ref)0.91 (0.78–1.07)1.06 (0.90–1.26)1.05 (0.88–1.25)1.03 (0.86–1.25).4221.06 (0.91–1.24)
       High-risk adenoma
      Ncases/Ncontrols141/9784138/9839158/9724155/9779166/9826
      Multivariable1 (ref)1.02 (0.80–1.31)1.22 (0.95–1.57)1.22 (0.94–1.59)1.32 (1.01–1.73).0221.28 (1.04–1.57)
      Total serrated lesions
      Ncases/Ncontrols471/9958470/9965465/9961491/9933458/9989
      Multivariable1 (ref)1.02 (0.89–1.17)1.01 (0.88–1.17)1.10 (0.95–1.27)1.05 (0.90–1.23).4051.05 (0.93–1.19)
       Small serrated lesion
      Ncases/Ncontrols396/9958397/9965407/9961427/9933388/9989
      Multivariable1 (ref)1.03 (0.88–1.20)1.06 (0.91–1.24)1.15 (0.98–1.35)1.07 (0.90–1.27).2771.08 (0.94–1.23)
       Large serrated lesion
      Ncases/Ncontrols45/995845/996531/996139/993336/9989
      Multivariable1 (ref)1.01 (0.66–1.53)0.67 (0.41–1.10)0.82 (0.51–1.31)0.77 (0.48–1.25).2400.79 (0.53–1.17)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols486/9592451/9628513/9569462/9597477/9613
      Multivariable1 (ref)0.98 (0.85–1.12)1.16 (1.01–1.34)1.09 (0.94–1.26)1.17 (1.00–1.36).0261.15 (1.02–1.30)
       Serrated lesion only
      Ncases/Ncontrols373/9592377/9628355/9569365/9597365/9613
      Multivariable1 (ref)1.03 (0.88–1.20)0.97 (0.82–1.13)1.01 (0.86–1.19)1.03 (0.87–1.22).7801.02 (0.89–1.17)
       Both adenoma and serrated lesion
      Ncases/Ncontrols98/959293/9628110/9569126/959793/9613
      Multivariable1 (ref)1.00 (0.74–1.34)1.24 (0.92–1.67)1.48 (1.09–2.00)1.18 (0.84–1.64).0971.24 (0.96–1.59)
      Glucose intake during adolescence (g/d)Per 35 g/d
      Corresponds to 5% of calorie intake in study participants.
      increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols586/9962579/9970579/9970593/9956572/9976
      Multivariable
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current sugar intake.
      1 (ref)1.04 (0.92–1.18)1.07 (0.94–1.21)1.13 (0.99–1.29)1.13 (0.98–1.29).0551.12 (1.00–1.25)
       Proximal adenoma
      Ncases/Ncontrols322/9777316/9803316/9780310/9762284/9830
      Multivariable1 (ref)1.04 (0.88–1.23)1.08 (0.91–1.28)1.10 (0.92–1.31)1.04 (0.86–1.26).6231.04 (0.89–1.21)
       Distal adenoma
      Ncases/Ncontrols238/9777233/9803226/9780253/9762255/9830
      Multivariable1 (ref)1.03 (0.86–1.25)1.02 (0.84–1.25)1.19 (0.97–1.45)1.22 (0.99–1.51).0281.22 (1.02–1.45)
       Rectal adenoma
      Ncases/Ncontrols84/977786/980396/978084/9762108/9830
      Multivariable1 (ref)1.07 (0.78–1.47)1.23 (0.90–1.68)1.11 (0.80–1.55)1.51 (1.08–2.11).0161.40 (1.06–1.84)
       Low-risk adenoma
      Ncases/Ncontrols353/9777321/9803327/9780327/9762300/9830
      Multivariable1 (ref)0.95 (0.81–1.11)1.00 (0.85–1.18)1.03 (0.87–1.23)0.99 (0.82–1.19).8311.02 (0.87–1.18)
       High-risk adenoma
      Ncases/Ncontrols135/9777159/9803139/9780153/9762172/9830
      Multivariable1 (ref)1.22 (0.96–1.56)1.09 (0.84–1.41)1.22 (0.94–1.58)1.37 (1.05–1.79).0321.26 (1.02–1.56)
      Total serrated lesions
      Ncases/Ncontrols455/9982467/9962469/9958494/9935470/9969
      Multivariable1 (ref)1.06 (0.92–1.22)1.07 (0.92–1.23)1.14 (0.99–1.33)1.12 (0.96–1.31).1101.11 (0.98–1.26)
       Small serrated lesion
      Ncases/Ncontrols386/9982397/9962405/9958427/9935400/9969
      Multivariable1 (ref)1.06 (0.91–1.23)1.09 (0.93–1.27)1.17 (1.00–1.37)1.13 (0.95–1.34).0971.12 (0.98–1.28)
       Large serrated lesion
      Ncases/Ncontrols43/998241/996235/995842/993535/9969
      Multivariable1 (ref)0.96 (0.62–1.50)0.81 (0.50–1.31)0.97 (0.61–1.54)0.81 (0.50–1.31).4370.86 (0.58–1.26)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols495/9598479/9603471/9609473/9582471/9607
      Multivariable1 (ref)1.02 (0.89–1.16)1.03 (0.90–1.18)1.06 (0.92–1.23)1.09 (0.93–1.27).2301.08 (0.95–1.22)
       Serrated lesion only
      Ncases/Ncontrols364/9598367/9603361/9609374/9582369/9607
      Multivariable1 (ref)1.03 (0.88–1.20)1.01 (0.86–1.18)1.06 (0.90–1.25)1.07 (0.90–1.27).4011.06 (0.92–1.22)
       Both adenoma and serrated lesion
      Ncases/Ncontrols91/9598100/9603108/9609120/9582101/9607
      Multivariable1 (ref)1.16 (0.87–1.55)1.29 (0.96–1.74)1.50 (1.11–2.02)1.37 (0.99–1.88).0261.33 (1.03–1.71)
      Added sugar intake during adolescence (g/d)Per 35 g/d
      Corresponds to 5% of calorie intake in study participants.
      increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols577/10004582/9939534/10021580/9963636/9907
      Multivariable
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current sugar intake.
      1 (ref)1.02 (0.90–1.15)0.93 (0.82–1.05)1.03 (0.91–1.17)1.17 (1.02–1.34).0151.08 (1.01–1.14)
       Proximal adenoma
      Ncases/Ncontrols301/9815329/9755289/9867295/9771334/9744
      Multivariable1 (ref)1.10 (0.93–1.30)0.97 (0.81–1.15)1.01 (0.85–1.21)1.18 (0.98–1.42).1621.06 (0.98–1.15)
       Distal adenoma
      Ncases/Ncontrols248/9815229/9755219/9867234/9771275/9744
      Multivariable1 (ref)0.94 (0.78–1.13)0.88 (0.72–1.06)0.97 (0.79–1.18)1.19 (0.97–1.46).0571.09 (1.00–1.20)
       Rectal adenoma
      Ncases/Ncontrols84/981586/975571/9867108/9771109/9744
      Multivariable1 (ref)1.06 (0.77–1.45)0.85 (0.61–1.19)1.35 (0.98–1.85)1.40 (0.99–1.96).0161.20 (1.03–1.39)
       Low-risk adenoma
      Ncases/Ncontrols332/9815331/9755297/9867327/9771341/9744
      Multivariable1 (ref)1.00 (0.85–1.17)0.89 (0.75–1.05)1.01 (0.86–1.20)1.10 (0.92–1.32).2341.05 (0.97–1.14)
       High-risk adenoma
      Ncases/Ncontrols144/9815147/9755135/9867152/9771180/9744
      Multivariable1 (ref)1.01 (0.80–1.28)0.90 (0.70–1.15)1.03 (0.80–1.32)1.21 (0.93–1.57).1131.10 (0.98–1.23)
      Total serrated lesions
      Ncases/Ncontrols444/10033453/9952461/9961495/9937502/9923
      Multivariable1 (ref)1.01 (0.88–1.16)1.02 (0.89–1.18)1.10 (0.95–1.27)1.15 (0.99–1.34).0361.07 (1.00–1.15)
       Small serrated lesion
      Ncases/Ncontrols379/10033381/9952400/9961430/9937425/9923
      Multivariable1 (ref)1.00 (0.86–1.16)1.05 (0.90–1.22)1.13 (0.97–1.32)1.15 (0.98–1.36).0361.08 (1.00–1.16)
       Large serrated lesion
      Ncases/Ncontrols35/1003344/995234/996138/993745/9923
      Multivariable1 (ref)1.22 (0.77–1.92)0.89 (0.54–1.45)0.98 (0.61–1.58)1.17 (0.73–1.89).7171.04 (0.85–1.28)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols486/9651477/9591434/9660475/9573517/9524
      Multivariable1 (ref)1.00 (0.87–1.14)0.90 (0.78–1.03)1.01 (0.88–1.17)1.13 (0.97–1.31).0771.06 (0.99–1.13)
       Serrated lesion only
      Ncases/Ncontrols353/9651348/9591361/9660390/9573383/9524
      Multivariable1 (ref)0.98 (0.84–1.14)0.99 (0.85–1.16)1.09 (0.93–1.28)1.09 (0.92–1.30).1521.05 (0.98–1.13)
       Both adenoma and serrated lesion
      Ncases/Ncontrols91/9651105/9591100/9660105/9573119/9524
      Multivariable1 (ref)1.13 (0.85–1.50)1.08 (0.80–1.45)1.15 (0.86–1.55)1.43 (1.05–1.95).0251.16 (1.02–1.33)
      Total sugar intake during adolescence (g/d)Per 35 g/d
      Corresponds to 5% of calorie intake in study participants.
      increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases/Ncontrols580/9969561/9988586/9963599/9950583/9964
      Multivariable
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current sugar intake.
      1 (ref)0.99 (0.88–1.12)1.06 (0.94–1.20)1.11 (0.98–1.26)1.13 (0.99–1.29).0241.07 (1.01–1.13)
       Proximal adenoma
      Ncases/Ncontrols316/9789303/9799312/9794321/9769296/9801
      Multivariable1 (ref)0.98 (0.83–1.16)1.04 (0.88–1.23)1.09 (0.92–1.30)1.07 (0.89–1.29).2811.04 (0.97–1.13)
       Distal adenoma
      Ncases/Ncontrols243/9789223/9799231/9794240/9769268/9801
      Multivariable1 (ref)0.94 (0.78–1.14)0.99 (0.81–1.20)1.06 (0.87–1.29)1.23 (1.00–1.50).0201.11 (1.02–1.21)
       Rectal adenoma
      Ncases/Ncontrols80/978985/979992/9794105/976996/9801
      Multivariable1 (ref)1.14 (0.83–1.55)1.29 (0.95–1.75)1.51 (1.11–2.06)1.45 (1.06–2.00).0071.20 (1.05–1.37)
       Low-risk adenoma
      Ncases/Ncontrols332/9789331/9799327/9794332/9769306/9801
      Multivariable1 (ref)1.01 (0.86–1.19)1.01 (0.85–1.19)1.05 (0.89–1.25)1.03 (0.86–1.23).6621.02 (0.94–1.10)
       High-risk adenoma
      Ncases/Ncontrols144/9789133/9799147/9794168/9769166/9801
      Multivariable1 (ref)0.97 (0.76–1.24)1.10 (0.87–1.41)1.30 (1.01–1.66)1.31 (1.02–1.68).0061.16 (1.04–1.29)
      Total serrated lesions
      Ncases/Ncontrols489/9948448/9990489/9927447/9989482/9952
      Multivariable1 (ref)0.93 (0.81–1.07)1.07 (0.93–1.23)0.98 (0.85–1.13)1.10 (0.95–1.27).1381.05 (0.99–1.12)
       Small serrated lesion
      Ncases/Ncontrols407/9948382/9990427/9927385/9989414/9952
      Multivariable1 (ref)0.96 (0.82–1.11)1.12 (0.97–1.30)1.02 (0.87–1.19)1.14 (0.98–1.34).0631.07 (1.00–1.14)
       Large serrated lesion
      Ncases/Ncontrols47/994842/999033/992743/998931/9952
      Multivariable1 (ref)0.91 (0.59–1.39)0.74 (0.46–1.18)0.94 (0.60–1.46)0.70 (0.44–1.13).1980.88 (0.72–1.07)
      Subtype of colorectal polyp
       Adenoma only
      Ncases/Ncontrols475/9585469/9632473/9587490/9612482/9583
      Multivariable1 (ref)1.01 (0.88–1.15)1.04 (0.90–1.19)1.09 (0.94–1.25)1.13 (0.97–1.30).0671.06 (1.00–1.13)
       Serrated lesion only
      Ncases/Ncontrols384/9585356/9632376/9587338/9612381/9583
      Multivariable1 (ref)0.94 (0.80–1.09)1.03 (0.88–1.20)0.93 (0.79–1.09)1.09 (0.93–1.27).3111.04 (0.97–1.11)
       Both adenoma and serrated lesion
      Ncases/Ncontrols105/958592/9632113/9587109/9612101/9583
      Multivariable1 (ref)0.91 (0.68–1.21)1.19 (0.90–1.57)1.20 (0.90–1.61)1.18 (0.87–1.60).1151.11 (0.98–1.26)
      a Corresponds to 5% of calorie intake in study participants.
      b Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current sugar intake.
      Supplementary Table 8Multivariable ORs and 95% CIs of Colorectal Adenoma Diagnosed By Colonoscopy
      After excluding participants with sigmoidoscopy only.
      Total fructose intake during adolescence, % of calorie, quintilePer 5% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Total adenoma
      Ncases540/9284534/9355562/9307552/9310553/9416
      Multivariable1 (ref)1.03 (0.90–1.17)1.13 (0.99–1.29)1.16 (1.01–1.34)1.18 (1.02–1.37).0121.16 (1.03–1.30)
       Proximal
      Ncases298/9146290/9221303/9165288/9176281/9288
      Multivariable1 (ref)1.02 (0.85–1.21)1.12 (0.94–1.34)1.11 (0.92–1.35)1.10 (0.90–1.36).2671.09 (0.93–1.28)
       Distal
      Ncases226/9146204/9221230/9165240/9176239/9288
      Multivariable1 (ref)0.93 (0.76–1.14)1.10 (0.89–1.35)1.20 (0.97–1.48)1.21 (0.97–1.52).0231.23 (1.03–1.47)
       Rectal
      Ncases73/914689/922180/916593/917696/9288
      Multivariable1 (ref)1.32 (0.96–1.83)1.25 (0.89–1.75)1.58 (1.12–2.24)1.68 (1.17–2.42).0041.49 (1.13–1.96)
       Low-risk adenoma
      Ncases326/9146296/9221323/9165291/9176306/9288
      Multivariable1 (ref)0.93 (0.79–1.10)1.06 (0.89–1.26)0.99 (0.82–1.19)1.07 (0.88–1.31).3791.07 (0.92–1.25)
       High-risk adenoma
      Ncases125/9146143/9221142/9165157/9176150/9288
      Multivariable1 (ref)1.20 (0.93–1.56)1.24 (0.95–1.62)1.45 (1.10–1.90)1.36 (1.02–1.81).0261.28 (1.03–1.58)
      SSB intake during adolescence, servingsPer 1 serving/d increase
      <1/week1–6/week1/day≥2/dayPtrend
      Total adenoma
      Ncases1150/191921131/20722256/3616153/2189
      Multivariable1 (ref)0.92 (0.84–1.01)1.22 (1.05–1.42)1.23 (1.00–1.50).0081.12 (1.03–1.21)
       Proximal
      Ncases619/18908591/20442140/355584/2156
      Multivariable1 (ref)0.90 (0.79–1.02)1.26 (1.03–1.55)1.28 (0.98–1.69).0181.14 (1.02–1.27)
       Distal
      Ncases473/18908483/20442106/355559/2156
      Multivariable1 (ref)0.95 (0.82–1.09)1.21 (0.96–1.53)1.13 (0.82–1.55).2201.08 (0.95–1.22)
       Rectal
      Ncases177/18908162/2044248/355532/2156
      Multivariable1 (ref)0.86 (0.68–1.08)1.54 (1.08–2.20)1.77 (1.11–2.80).0021.33 (1.11–1.60)
       Low-risk adenoma
      Ncases637/18908653/20442145/355584/2156
      Multivariable1 (ref)0.97 (0.86–1.09)1.27 (1.03–1.55)1.26 (0.97–1.65).0231.13 (1.02–1.25)
       High-risk adenoma
      Ncases305/18908287/2044270/355541/2156
      Multivariable1 (ref)0.84 (0.70–1.00)1.19 (0.90–1.58)1.10 (0.74–1.62).3661.07 (0.92–1.26)
      NOTE. Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake.
      a After excluding participants with sigmoidoscopy only.
      Supplementary Table 9Multivariable ORs and 95% CIs of Proximal Serrated Lesions (n = 802) and Large Proximal Serrated Lesions (n = 145)
      Total fructose intake during adolescence, % of calorie, quintilePer 5% of calorie increase
      Q1Q2Q3Q4Q5Ptrend
      Proximal serrated lesions
       Ncases156/9951176/9993176/9945144/9934150/9983
       Model 1
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      1 (ref)1.12 (0.90–1.40)1.14 (0.91–1.42)0.94 (0.74–1.18)0.98 (0.78–1.24).440.94 (0.79–1.11)
       Model 2
      Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      1 (ref)1.12 (0.90–1.40)1.14 (0.91–1.42)0.94 (0.75–1.19)1.00 (0.80–1.26).560.95 (0.80–1.12)
       Model 3
      Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake in model 2.
      1 (ref)1.08 (0.85–1.36)1.07 (0.84–1.36)0.88 (0.67–1.15)0.93 (0.70–1.23).300.89 (0.72–1.11)
      Large proximal serrated lesions
      ≥1 cm in size.
       Ncases30/995135/999332/994517/993431/9983
       Model 11 (ref)1.15 (0.71–1.88)1.07 (0.65–1.77)0.57 (0.31–1.03)1.04 (0.63–1.72).510.87 (0.58–1.31)
       Model 21 (ref)1.16 (0.71–1.90)1.09 (0.66–1.81)0.59 (0.33–1.07)1.11 (0.67–1.83).690.92 (0.62–1.38)
       Model 31 (ref)1.13 (0.67–1.92)1.01 (0.59–1.75)0.53 (0.27–1.03)0.99 (0.57–1.71).460.84 (0.54–1.32)
      SSB intake during adolescence, servingsPer 1 serving/d increase
      <1/week1–6/week1/day≥2/dayPtrend
      Proximal serrated lesions
       Ncases347/20667353/2192160/388136/2322
       Model 11 (ref)0.96 (0.82–1.11)0.94 (0.71–1.24)0.94 (0.66–1.34).660.97 (0.85–1.11)
       Model 21 (ref)0.96 (0.82–1.12)0.93 (0.71–1.23)0.94 (0.66–1.34).630.97 (0.84–1.11)
       Model 31 (ref)0.99 (0.84–1.17)1.00 (0.74–1.34)1.08 (0.74–1.58).731.03 (0.88–1.20)
      Large proximal serrated lesions
       Ncases64/2066766/219219/38816/2322
       Model 11 (ref)0.97 (0.69–1.38)0.77 (0.38–1.54)0.84 (0.36–1.95).530.90 (0.64–1.26)
       Model 21 (ref)0.99 (0.70–1.40)0.75 (0.37–1.52)0.84 (0.35–1.98).530.90 (0.64–1.26)
       Model 31 (ref)0.96 (0.66–1.38)0.71 (0.34–1.50)0.83 (0.33–2.09).540.89 (0.61–1.30)
      a Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms).
      b Additionally adjusted for family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current).
      c Additionally adjusted for adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake in model 2.
      d ≥1 cm in size.
      Supplementary Table 10Multivariable ORs and 95% CIs of Total Adenoma According to Total Fructose and SSB Intake During Adolescence by Family History, Birth Year, Lifestyle, and Dietary Factors
      Total fructose
      Comparison of total fructose intake between the highest vs. lowest quintiles (referent).
      SSB
      Comparison of SSB intake between categories of ≥1 serving/d vs <1 serving/wk (referent).
      Ncases/NcontrolsOR (95% CI)
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      PinterNcases/NcontrolsOR (95% CI)
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      Pinter
      Family history of CRC
       No1994/364201.10 (0.92–1.31).242523/416341.21 (1.03–1.42).46
       Yes915/134141.40 (1.08–1.82)330/71901.17 (0.92–1.48)
      Birth year
       1946–19592572/424701.19 (1.02–1.39).241957/356911.17 (1.02–1.35).70
       1960–1965337/73641.26 (0.82–1.92)896/131331.28 (0.87–1.88)
      Lifestyle factors during adolescence
       BMI
      ≤22.5 kg/m22198/387551.22 (1.03–1.44).692161/380741.19 (1.02–1.39).88
      >22.5 kg/m2711/110791.19 (0.89–1.60)692/107501.26 (0.96–1.65)
       Physical activity
      High physical activity was defined as the highest tertile (≥59 MET-h/wk), and low physical activity as 2 bottom tertiles (<59 MET-h/wk).
      Low1952/317211.23 (1.04–1.47).491912/310441.23 (1.04–1.44).15
      High878/159041.11 (0.84–1.45)863/156311.10 (0.87–1.40)
       Smoking
      No2214/385561.19 (1.01–1.41).612170/378191.17 (1.00–1.37).32
      Yes695/112781.22 (0.91–1.63)683/110051.36 (1.05–1.76)
       Alcohol intake
      <5 g/d1680/285201.21 (1.00–1.46).901646/279781.27 (1.07–1.52).57
      ≥5 g/d1219/210581.18 (0.94–1.48)1197/205971.13 (0.93–1.39)
      Dietary intake during adolescence
       Fruit intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1502/248771.51 (1.26–1.82)<.0011479/244221.34 (1.12–1.60).028
      High1407/249570.87 (0.69–1.09)1374/244021.05 (0.85–1.29)
       Fruit juice intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1459/250321.21 (1.00–1.48).751432/244991.16 (0.96–1.39).89
      High1446/247181.19 (0.93–1.51)1417/242491.25 (1.04–1.52)
       Fruit/fruit juice intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      High/low506/91900.74 (0.52–1.04)<.001496/89610.97 (0.67–1.40).017
      High/high901/157540.95 (0.66–1.37)878/154331.10 (0.85–1.42)
      Low/low953/158421.52 (1.20–1.91)936/155381.24 (0.99–1.55)
      Low/high545/89641.59 (1.13–2.25)539/88161.63 (1.21–2.21)
       Vegetable intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1501/248691.37 (1.13–1.67).0951477/244041.39 (1.16–1.68).014
      High1408/249651.00 (0.80–1.23)1376/244201.00 (0.82–1.22)
       Fiber intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1553/248241.37 (1.13–1.65).0291529/244101.39 (1.17–1.65).007
      High1356/250101.04 (0.82–1.31)1324/244140.88 (0.70–1.11)
       Prudent dietary pattern score
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1482/237061.37 (1.14–1.65).0121482/237061.30 (1.10–1.54).15
      High1311/238770.98 (0.79–1.20)1311/238771.02 (0.81–1.29)
       Western dietary pattern score
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low1333/238550.94 (0.76–1.16).0021333/238551.22 (1.00–1.48).70
      High1460/237281.44 (1.19–1.74)1460/237281.18 (0.98–1.43)
      a Comparison of total fructose intake between the highest vs. lowest quintiles (referent).
      b Comparison of SSB intake between categories of ≥1 serving/d vs <1 serving/wk (referent).
      c Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      d High physical activity was defined as the highest tertile (≥59 MET-h/wk), and low physical activity as 2 bottom tertiles (<59 MET-h/wk).
      e Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Supplementary Table 11Multivariable ORs and 95% CIs of High-Risk Colorectal Adenoma According to Total Fructose and SSB Intake During Adolescence by Family History, Birth Year, Lifestyle, and Dietary Factors
      Total fructose
      Comparison of total fructose intake between the highest vs. lowest quintiles (referent).
      SSB
      Comparison of SSB intake between categories of ≥1 serving/d vs. <1 serving/wk (referent).
      Ncases/NcontrolsOR (95% CI)
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      PinterNcases/NcontrolsOR (95% CI)
      Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      Pinter
      Family history of CRC
       No527/359161.32 (0.95–1.84).26515/351971.14 (0.83–1.55).83
       Yes231/130361.45 (0.85–2.48)227/127631.14 (0.73–1.80)
      Birth year
       1946–1959667/416431.35 (1.00–1.83).98655/408241.14 (0.88–1.49).43
       1960–196591/73092.14 (0.91–5.02)87/71361.01 (0.46–2.19)
      Lifestyle factors during adolescence
       BMI
      ≤22.5 kg/m2582/380841.38 (1.01–1.90).52574/374171.08 (0.81–1.44).36
      >22.5 kg/m2176/108681.40 (0.74–2.63)168/105431.40 (0.83–2.37)
       Physical activity
      High physical activity was defined as the highest tertile (≥59 MET-hr/wk), and low physical activity as 2 bottom tertiles (<59 MET-h/wk).
      Low524/31111.42 (1.01–2.00).59510/304441.11 (0.81–1.52).91
      High212/156501.27 (0.75–2.14)210/153831.09 (0.69–1.73)
       Smoking
      No562/378681.29 (0.92–1.79).20551/371461.07 (0.79–1.45).21
      Yes196/110841.86 (1.07–3.22)191/108141.63 (1.01–2.61)
       Alcohol intake
      <5 g/d428/280071.45 (1.01–2.07).10418/274761.29 (0.93–1.78).50
      ≥5 g/d328/206901.25 (0.79–1.98)322/202361.01 (0.68–1.50)
      Dietary intake during adolescence
       Fruit intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low397/244431.76 (1.23–2.52).36391/239961.30 (0.92–1.82).32
      High361/245090.97 (0.61–1.55)351/239640.97 (0.66–1.44)
       Fruit juice intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low375/246161.56 (1.07–2.28).59368/240921.28 (0.90–1.82).51
      High382/242521.23 (0.77–1.98)373/237921.05 (0.73–1.50)
       Vegetable intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low399/244572.07 (1.40–3.04).009391/239971.82 (1.30–2.56).003
      High359/244950.86 (0.57–1.29)351/239630.60 (0.40–0.90)
       Fiber intake
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low406/243531.44 (0.99–2.10).24399/239481.41 (1.02–1.95).027
      High352/245991.31 (0.84–2.04)343/240120.70 (0.44–1.12)
       Prudent dietary pattern score
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low396/232691.82 (1.27–2.62).020396/232691.40 (1.02–1.92).12
      High335/234681.02 (0.68–1.53)335/234680.76 (0.47–1.21)
       Western dietary pattern score
      Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Low328/234321.06 (0.71–1.60).29328/234321.02 (0.69–1.49).59
      High403/233051.76 (1.22–2.55)403/233051.33 (0.94–1.88)
      a Comparison of total fructose intake between the highest vs. lowest quintiles (referent).
      b Comparison of SSB intake between categories of ≥1 serving/d vs. <1 serving/wk (referent).
      c Adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current total fructose or SSB intake except for the stratifying variable of each stratum.
      d High physical activity was defined as the highest tertile (≥59 MET-hr/wk), and low physical activity as 2 bottom tertiles (<59 MET-h/wk).
      e Cutoff values were median intake (fruits, 1.3 serving/d; fruit juice, 0.4 serving/d; vegetables, 2.8 serving/d; fiber, 20.2 g/d).
      Supplementary Table 12ORs and 95% CIs
      Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, and western dietary pattern score during adolescence.
      of Colorectal Adenoma According to Joint Categories of Total Fructose and SSB Intake During Adolescence and Adulthood
      Joint categories of intake (adolescence/adulthood)
      Low/lowLow/highHigh/lowHigh/high
      Total fructose
       Total adenoma
      Ncases/Ncontrols1196/20365542/9543603/9564568/10362
      OR (95% CI)1 (ref)1.06 (0.94–1.18)1.16 (1.04–1.30)1.08 (0.96–1.22)
       Rectal adenoma
      Ncases/Ncontrols180/2000578/9362105/939695/10189
      OR (95% CI)1 (ref)0.91 (0.68–1.20)1.34 (1.02–1.75)1.10 (0.82–1.48)
       High-risk adenoma
      Ncases/Ncontrols301/20005131/9362165/9396161/10189
      OR (95% CI)1 (ref)0.98 (0.78–1.22)1.25 (1.01–1.54)1.17 (0.93–1.47)
      SSBs
      SSB intake, high: ≥1 serving/day; low: <1 serving/week.
       Total adenoma
      Ncases/Ncontrols2237/39026186/3545330/458898/1528
      OR (95% CI)1 (ref)0.90 (0.76–1.06)1.27 (1.12–1.45)1.13 (0.90–1.42)
       Rectal adenoma
      Ncases/Ncontrols331/3835431/347465/450018/1496
      OR (95% CI)1 (ref)0.95 (0.63–1.43)1.76 (1.31–2.35)1.35 (0.80–2.30)
       High-risk adenoma
      Ncases/Ncontrols575/3835451/347480/450035/1496
      OR (95% CI)1 (ref)0.88 (0.64–1.21)1.20 (0.93–1.55)1.40 (0.95–2.07)
      a Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, and western dietary pattern score during adolescence.
      b SSB intake, high: ≥1 serving/day; low: <1 serving/week.
      Supplementary Table 13Multivariable ORs and 95% CIs of Adenoma Associated With SSBs and Foods for SSBs
      Alternative beverage or food for SSBs (alternative: SSBs)
      Fruit juice (1:1)Fruit (2:2)Total dairy (2:2)
      OR (95% CI)POR (95% CI)POR (95% CI)P
      Total adenoma0.95 (0.82–1.10).500.86 (0.68–1.09).210.82 (0.64–1.04).11
      Proximal adenoma0.90 (0.73–1.10).300.75 (0.54–1.05).0920.80 (0.58–1.11).19
      Distal adenoma1.03 (0.82–1.29).811.04 (0.73–1.49).820.94 (0.65–1.36).74
      Rectal adenoma0.81 (0.57–1.16).250.61 (0.35–1.07).0870.53 (0.30–0.94).029
      Low-risk adenoma0.90 (0.74–1.10).310.88 (0.64–1.19).410.84 (0.61–1.16).29
      High-risk adenoma1.04 (0.78–1.38).810.90 (0.56–1.43).650.73 (0.45–1.17).19
      NOTE. Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, western dietary pattern score during adolescence, and current SSB intake.
      Figure thumbnail fx2
      Supplementary Figure 1Joint associations of total fructose and SSB intake between adolescence and adulthood with risk of colorectal adenoma in the Nurses’ Health Study II, 1998–2015. Data were adjusted for age, time period of endoscopy, number of endoscopies (continuous), time since most recent endoscopy (continuous), reason for endoscopy (screening/symptoms), family history of CRC, menopausal status/menopausal hormone use, current aspirin use ≥2 times/wk, history of type 2 diabetes, adult height (continuous), BMI (at age 18 y, current), smoking status (adolescent, current), alcohol consumption (at 18–22 y, current), physical activity (adolescent, current), adolescent and current (adult) dietary intake (total calorie, total calcium, vitamin D, total folate, total fiber, fruits, vegetables, and dairy), current total red meat intake, and western dietary pattern score during adolescence. ∗P ≤ .03. aP ≥ .21. bP ≥ .36.

      References

        • Arnold M.
        • Sierra M.S.
        • Laversanne M.
        • et al.
        Global patterns and trends in colorectal cancer incidence and mortality.
        Gut. 2017; 66: 683-691
        • Siegel R.L.
        • Jakubowski C.D.
        • Fedewa S.A.
        • et al.
        Colorectal cancer in the young: epidemiology, prevention, management.
        Am Soc Clin Oncol Educ Book. 2020; 40: 1-14
        • Keum N.
        • Giovannucci E.
        Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 713-732
        • Siegel R.L.
        • Miller K.D.
        • Goding Sauer A.
        • et al.
        Colorectal cancer statistics, 2020.
        CA Cancer J Clin. 2020; 70: 145-164
      1. SEER Cancer Stat Facts: CRC. Bethesda, MD: National Cancer Institute. Available at seer.cancer.gov/statfacts/html/colorect.html. Accessed Oct 12, 2020.

        • American Cancer Society
        Colorectal Cancer Facts & Figures 2020–2022.
        American Cancer Society, Atlanta, GA2020
        • Bray G.A.
        • Nielsen S.J.
        • Popkin B.M.
        Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
        Am J Clin Nutr. 2004; 79: 537-543
        • Marriott B.P.
        • Cole N.
        • Lee E.
        National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.
        J Nutr. 2009; 139: 1228s-1235s
      2. Healthy Food America. Sugary drinks in America: who's drinking what and how much? Available at healthyfoodamerica.org/sugary_drinks_in_america_who_s_drinking_what_and_how_much. Accessed Oct 21, 2020.

        • Cavadini C.
        • Siega-Riz A.M.
        • Popkin B.M.
        US adolescent food intake trends from 1965 to 1996.
        West J Med. 2000; 173: 378-383
        • Rosinger A.
        • Herrick K.
        • Gahche J.
        • et al.
        Sugar-sweetened beverage consumption among U.S. youth, 2011–2014.
        NCHS Data Brief. 2017; 271: 1-8
        • Malik V.S.
        • Hu F.B.
        Sugar-sweetened beverages and cardiometabolic health: an update of the evidence.
        Nutrients. 2019; 11: 1840
        • Yang L.
        • Bovet P.
        • Liu Y.
        • et al.
        Consumption of carbonated soft drinks among young adolescents aged 12 to 15 years in 53 low- and middle-income countries.
        Am J Public Health. 2017; 107: 1095-1100
        • Yu Z.
        • Ley S.H.
        • Sun Q.
        • et al.
        Cross-sectional association between sugar-sweetened beverage intake and cardiometabolic biomarkers in US women.
        Br J Nutr. 2018; 119: 570-580
        • World Cancer Research Fund/American Institute for Cancer Research
        Diet, nutrition, physical activity and cancer: a global perspective.
        Continuous Update Project Expert Report, 2018 (Available at)
        dietandcancerreport.org
        Date accessed: July 17, 2020
        • Giovannucci E.
        Insulin, insulin-like growth factors and colon cancer: a review of the evidence.
        J Nutr. 2001; 131: 3109s-3120s
        • Kaaks R.
        • Toniolo P.
        • Akhmedkhanov A.
        • et al.
        Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women.
        J Natl Cancer Inst. 2000; 92: 1592-1600
        • Zhang X.
        • Albanes D.
        • Beeson W.L.
        • et al.
        Risk of colon cancer and coffee, tea, and sugar-sweetened soft drink intake: pooled analysis of prospective cohort studies.
        J Natl Cancer Inst. 2010; 102: 771-783
        • Imperial College London Continuous Update Project
        World Cancer Research Fund International Systematic Literature Review: The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer.
        2017 (Available at wcrf.org/sites/default/files/colorectal-cancer-slr.pdf. Accessed July 15, 2020)
        • Nimptsch K.
        • Wu K.
        Is timing important? The role of diet and lifestyle during early life on colorectal neoplasia.
        Curr Colorectal Cancer Rep. 2018; 14: 1-11
        • Hannon T.S.
        • Janosky J.
        • Arslanian S.A.
        Longitudinal study of physiologic insulin resistance and metabolic changes of puberty.
        Pediatr Res. 2006; 60: 759-763
        • Strum W.B.
        Colorectal adenomas.
        N Engl J Med. 2016; 374: 1065-1075
        • Bao Y.
        • Bertoia M.L.
        • Lenart E.B.
        • et al.
        Origin, methods, and evolution of the three nurses' health studies.
        Am J Public Health. 2016; 106: 1573-1581
        • Maruti S.S.
        • Feskanich D.
        • Colditz G.A.
        • et al.
        Adult recall of adolescent diet: reproducibility and comparison with maternal reporting.
        Am J Epidemiol. 2005; 161: 89-97
        • Maruti S.S.
        • Feskanich D.
        • Rockett H.R.
        • et al.
        Validation of adolescent diet recalled by adults.
        Epidemiology (Cambridge, Mass.). 2006; 17: 226-229
        • Hu F.B.
        • Rimm E.
        • Smith-Warner S.A.
        • et al.
        Reproducibility and validity of dietary patterns assessed with a food-frequency questionnaire.
        Am J Clin Nutr. 1999; 69: 243-249
        • Johnson R.K.
        • Appel L.J.
        • Brands M.
        • et al.
        Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association.
        Circulation. 2009; 120: 1011-1020
        • US Department of Agriculture
        Composition of foods: raw, processed, and prepared, 1963–1980. (Agricultural handbook no. 8).
        US Department of Agriculture, Washington, DC1980
        • Willett W.
        Nutritional epidemiology.
        Oxford University Press USA, New York2013
        • Willett W.
        • Stampfer M.J.
        Total energy intake: implications for epidemiologic analyses.
        Am J Epidemiol. 1986; 124: 17-27
        • U.S. Department of Agriculture and U.S. Department of Health and Human Services
        Dietary guidelines for Americans, 2020–2025.
        9th Edition. December 2020 (Available at) (Accessed Jan 30, 2021)
        • Hu F.B.
        Dietary pattern analysis: a new direction in nutritional epidemiology.
        Curr Opin Lipidol. 2002; 13: 3-9
        • He X.
        • Hang D.
        • Wu K.
        • et al.
        Long-term risk of colorectal cancer after removal of conventional adenomas and serrated polyps.
        Gastroenterology. 2020; 158: 852-861.e4
        • Giovannucci E.
        • Ascherio A.
        • Rimm E.B.
        • et al.
        Physical activity, obesity, and risk for colon cancer and adenoma in men.
        Ann Intern Med. 1995; 122: 327-334
        • Gupta S.
        • Lieberman D.
        • Anderson J.C.
        • et al.
        Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.
        Gastroenterology. 2020; 158: 1131-1153.e5
        • Gill P.
        • Wang L.M.
        • Bailey A.
        • et al.
        Reporting trends of right-sided hyperplastic and sessile serrated polyps in a large teaching hospital over a 4-year period (2009–2012).
        J Clin Pathol. 2013; 66: 655-658
        • Maruti S.S.
        • Willett W.C.
        • Feskanich D.
        • et al.
        A prospective study of age-specific physical activity and premenopausal breast cancer.
        J Natl Cancer Inst. 2008; 100: 728-737
        • Rezende L.F.M.
        • Lee D.H.
        • Keum N.
        • et al.
        Physical activity during adolescence and risk of colorectal adenoma later in life: results from the Nurses' Health Study II.
        Br J Cancer. 2019; 121: 86-94
        • Ainsworth B.E.
        • Haskell W.L.
        • Herrmann S.D.
        • et al.
        2011 Compendium of Physical Activities: a second update of codes and MET values.
        Med Sci Sports Exerc. 2011; 43: 1575-1581
        • Andersen P.K.
        • Gill R.D.
        Cox's regression model for counting processes: a large sample study.
        Ann Statist. 1982; 10: 1100-1120
        • Bernstein A.M.
        • de Koning L.
        • Flint A.J.
        • et al.
        Soda consumption and the risk of stroke in men and women.
        Am J Clin Nutr. 2012; 95: 1190-1199
        • Michels K.B.
        • Willett W.C.
        Self-administered semiquantitative food frequency questionnaires: patterns, predictors, and interpretation of omitted items.
        Epidemiology. 2009; 20: 295-301
        • Pacheco L.S.
        • Anderson C.A.M.
        • Lacey Jr., J.V.
        • et al.
        Sugar-sweetened beverages and colorectal cancer risk in the California Teachers Study.
        PLoS One. 2019; 14e0223638
        • Vigneri P.G.
        • Tirrò E.
        • Pennisi M.S.
        • et al.
        The Insulin/IGF System in colorectal cancer development and resistance to therapy.
        Front Oncol. 2015; 5: 230
        • Wu J.
        • Cai Q.
        • Li H.
        • et al.
        Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men's Health Study.
        Carcinogenesis. 2013; 34: 2799-2803
        • de Koning L.
        • Malik V.S.
        • Kellogg M.D.
        • et al.
        Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men.
        Circulation. 2012; 125: 1735-1741, s1
        • Jang C.
        • Hui S.
        • Lu W.
        • et al.
        The small intestine converts dietary fructose into glucose and organic acids.
        Cell Metab. 2018; 27: 351-361.e3
        • Zhao S.
        • Jang C.
        • Liu J.
        • et al.
        Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
        Nature. 2020; 579: 586-591
        • Goncalves M.D.
        • Lu C.
        • Tutnauer J.
        • et al.
        High-fructose corn syrup enhances intestinal tumor growth in mice.
        Science. 2019; 363: 1345-1349
        • Do M.H.
        • Lee E.
        • Oh M.J.
        • et al.
        High-glucose or -fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change.
        Nutrients. 2018; 10: 761
        • Di Rienzi S.C.
        • Britton R.A.
        Adaptation of the gut microbiota to modern dietary sugars and sweeteners.
        Adv Nutr. 2020; 11: 616-629
        • Wong S.H.
        • Yu J.
        Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 690-704
        • Song M.
        • Chan A.T.
        • Sun J.
        Influence of the gut microbiome, diet, and environment on risk of colorectal cancer.
        Gastroenterology. 2020; 158: 322-340
        • Giovannucci E.
        A framework to understand diet, physical activity, body weight, and cancer risk.
        Cancer Causes Control. 2018; 29: 1-6
        • Bleich S.N.
        • Vercammen K.A.
        • Koma J.W.
        • et al.
        Trends in beverage consumption among children and adults, 2003–2014.
        Obesity (Silver Spring). 2018; 26: 432-441
        • Frazier A.L.
        • Willett W.C.
        • Colditz G.A.
        Reproducibility of recall of adolescent diet: Nurses' Health Study (United States).
        Cancer Causes Control. 1995; 6: 499-506
        • Zhang X.
        • Keum N.
        • Wu K.
        • et al.
        Calcium intake and colorectal cancer risk: results from the nurses' health study and health professionals follow-up study.
        Int J Cancer. 2016; 139: 2232-2242