Germline Genetic Features of Young Individuals With Colorectal Cancer

Published:November 13, 2017DOI:

      Background & Aims

      The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.


      We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.


      Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.


      Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.


      Abbreviations used in this paper:

      CRC (colorectal cancer), FAP (familial adenomatous polyposis), FDR (first-degree relative), MMR (mismatch repair), MSI (microsatellite instability), NGS (next-generation sequencing), VUS (variant of uncertain significance)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Edwards B.K.
        • Ward E.
        • Kohler B.A.
        • et al.
        Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates.
        Cancer. 2010; 116: 544-573
        • Meyer J.E.
        • Narang T.
        • Schnoll-Sussman F.H.
        • et al.
        Increasing incidence of rectal cancer in patients aged younger than 40 years: an analysis of the surveillance, epidemiology, and end results database.
        Cancer. 2010; 116: 4354-4359
        • Siegel R.L.
        • Jemal A.
        • Ward E.M.
        Increase in incidence of colorectal cancer among young men and women in the United States.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 1695-1698
        • Bailey C.E.
        • Hu C.Y.
        • You Y.N.
        • et al.
        Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975–2010.
        JAMA Surg. 2015; 150: 17-22
        • Siegel R.L.
        • Fedewa S.A.
        • Anderson W.F.
        • et al.
        Colorectal cancer incidence patterns in the United States, 1974–2013.
        J Natl Cancer Inst. 2017; 109
        • Abdelsattar Z.M.
        • Wong S.L.
        • Regenbogen S.E.
        • et al.
        Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening.
        Cancer. 2016; 122: 929-934
        • Levin B.
        • Lieberman D.A.
        • McFarland B.
        • et al.
        • American Cancer Society Colorectal Cancer Advisory Group, US Multi-Society Task Force, American College of Radiology Colon Cancer Committee
        Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.
        Gastroenterology. 2008; 134: 1570-1595
        • Jasperson K.W.
        • Tuohy T.M.
        • Neklason D.W.
        • Burt R.W.
        Hereditary and familial colon cancer.
        Gastroenterology. 2010; 138: 2044-2058
        • Hampel H.
        • Frankel W.L.
        • Martin E.
        • et al.
        Feasibility of screening for Lynch syndrome among patients with colorectal cancer.
        J Clin Oncol. 2008; 26: 5783-5788
        • Moreira L.
        • Balaguer F.
        • Lindor N.
        • et al.
        Identification of Lynch syndrome among patients with colorectal cancer.
        JAMA. 2012; 308: 1555-1565
        • Aaltonen L.A.
        • Salovaara R.
        • Kristo P.
        • et al.
        Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.
        N Engl J Med. 1998; 338: 1481-1487
        • Yurgelun M.B.
        • Kulke M.H.
        • Fuchs C.S.
        • et al.
        Cancer susceptibility gene mutations in individuals with colorectal cancer.
        J Clin Oncol. 2017; 35: 1086-1095
        • Evaluation of Genomic Applications in Prevention Working Group
        Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives.
        Genet Med. 2009; 11: 35-41
        • Grover S.
        • Kastrinos F.
        • Steyerberg E.W.
        • et al.
        Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.
        JAMA. 2012; 308: 485-492
        • Syngal S.
        • Brand R.E.
        • Church J.M.
        • et al.
        • American College of Gastroenterology
        ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
        Am J Gastroenterol. 2015; 110 (quiz 63): 223-262
        • Giardiello F.M.
        • Allen J.I.
        • Axilbund J.E.
        • et al.
        • Cancer US Multi-Society Task Force on Colorectal Cancer
        Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.
        Gastroenterology. 2014; 147: 502-526
      1. National Comprehensive Cancer Network. Genetic/familial high risk assessment: breast and/or ovarian and colorectal. NCCN Clinical Practice Guidelines in Oncology. 2016; v. 2.2017. Available at:

        • Broderick P.
        • Dobbins S.E.
        • Chubb D.
        • et al.
        Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients—a systematic review.
        Gastroenterology. 2017; 152: 75-77.e4
        • Yurgelun M.B.
        • Allen B.
        • Kaldate R.R.
        • et al.
        Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome.
        Gastroenterology. 2015; 149: 604-613.e20
        • Walsh T.
        • Casadei S.
        • Lee M.K.
        • et al.
        Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
        Proc Natl Acad Sci U S A. 2011; 108: 18032-18037
        • Kurian A.W.
        • Hare E.E.
        • Mills M.A.
        • et al.
        Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.
        J Clin Oncol. 2014; 32: 2001-2009
        • Cragun D.
        • Radford C.
        • Dolinsky J.S.
        • et al.
        Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory.
        Clin Genet. 2014; 86: 510-520
        • Limburg P.J.
        • Harmsen W.S.
        • Chen H.H.
        • et al.
        Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.
        Clin Gastroenterol Hepatol. 2011; 9: 497-502
        • Giraldez M.D.
        • Balaguer F.
        • Bujanda L.
        • et al.
        MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer.
        Clin Cancer Res. 2010; 16: 5402-5413
        • Chang D.T.
        • Pai R.K.
        • Rybicki L.A.
        • et al.
        Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features.
        Mod Pathol. 2012; 25: 1128-1139
        • Terdiman J.P.
        • Levin T.R.
        • Allen B.A.
        • et al.
        Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: high-risk clinic versus population-based registry.
        Gastroenterology. 2002; 122: 940-947
        • Goel A.
        • Nagasaka T.
        • Spiegel J.
        • et al.
        Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer.
        Clin Gastroenterol Hepatol. 2010; 8: 966-971
        • Chen S.
        • Wang W.
        • Lee S.
        • et al.
        Prediction of germline mutations and cancer risk in the Lynch syndrome.
        JAMA. 2006; 296: 1479-1487
        • Mork M.E.
        • You Y.N.
        • Ying J.
        • et al.
        High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer.
        J Clin Oncol. 2015; 33: 3544-3549
        • Pearlman R.
        • Frankel W.L.
        • Swanson B.
        • Ohio Colorectal Cancer Prevention Initiative Study Group
        Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer.
        JAMA Oncol. 2017; 3: 464-471
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        • ACMG Laboratory Quality Assurance Committee
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Kastrinos F.
        • Steyerberg E.W.
        • Mercado R.
        • et al.
        The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.
        Gastroenterology. 2011; 140: 73-81
        • Yurgelun M.B.
        • Masciari S.
        • Joshi V.A.
        • et al.
        • Colon Cancer Family Registry
        Germline TP53 mutations in patients with early-onset colorectal cancer in the Colon Cancer Family Registry.
        JAMA Oncol. 2015; 1: 214-221
        • Pujol P.
        • Lyonnet D.S.
        • Frebourg T.
        • et al.
        Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.
        Breast Cancer Res Treat. 2013; 141: 135-144
      2. Idos G KA, McDonnel K, et al. The GI gap in genetic testing for inherited susceptibility to cancer. American College of Gastroenterology Annual Meeting, Abstract P159. [Abstract]. 2015.

      3. National Comprehensive Cancer Network. Genetic/familial high risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology. 2016; v. 2.2016. Available at:

        • Robson M.E.
        • Bradbury A.R.
        • Arun B.
        • et al.
        American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
        J Clin Oncol. 2015; 33: 3660-3667
        • Gallego C.J.
        • Shirts B.H.
        • Bennette C.S.
        • et al.
        Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis.
        J Clin Oncol. 2015; 33: 2084-2091
        • Guindalini R.S.
        • Win A.K.
        • Gulden C.
        • et al.
        Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.
        Gastroenterology. 2015; 149: 1446-1453
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Colorectal cancer mortality rates in adults aged 20 to 54 years in the United States, 1970–2014.
        JAMA. 2017; 318: 572-574
        • Luba D.G.
        • DiSario J.A.
        • Rock C.
        • et al.
        Community practice implementation of a self-administered version of PREMM1,2,6 to assess risk for Lynch syndrome.
        Clin Gastroenterol Hepatol. 2018; 16: 49-58
        • Kastrinos F.
        • Uno H.
        • Ukaegbu C.
        • et al.
        Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome.
        J Clin Oncol. 2017; 35: 2165-2172
        • Haraldsdottir S.
        • Rafnar T.
        • Frankel W.L.
        • et al.
        Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.
        Nat Commun. 2017; 8: 14755
        • Goodenberger M.L.
        • Thomas B.C.
        • Riegert-Johnson D.
        • et al.
        PMS2 monoallelic mutation carriers: the known unknown.
        Genet Med. 2016; 18: 13-19
        • Win A.K.
        • Jenkins M.A.
        • Dowty J.G.
        • et al.
        Prevalence and penetrance of major genes and polygenes for colorectal cancer.
        Cancer Epidemiol Biomarkers Prev. 2017; 26: 404-412
        • Ahnen D.J.
        • Wade S.W.
        • Jones W.F.
        • et al.
        The increasing incidence of young-onset colorectal cancer: a call to action.
        Mayo Clin Proc. 2014; 89: 216-224
        • Yurgelun M.B.
        • Boland C.R.
        “New” cancer genes and inherited colorectal cancer risk: caveat emptor.
        Gastroenterology. 2017; 152: 12-13