Gastroenterology
Volume 132, Issue 1 , Pages 441-443, January 2007

Methionine Intake and Pancreatic Cancer Risk: Digesting the Evidence

  • Albert B. Lowenfels

      Affiliations

    • Department of Surgery, Department of Community and Preventive Medicine, New York Medical College, Valhalla, New York
    • Corresponding Author InformationAddress requests for reprints to Albert B. Lowenfels, MD, Department of Surgery, Department of Community and Preventive Medicine, New York Medical College, Valhalla, New York 10595. fax: (914) 594-4576.
    • ,
  • Patrick Maisonneuve

      Affiliations

    • Department of Community and Preventive Medicine, New York Medical College, Valhalla, New York, Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

Article Outline

 

See “Methionine and vitamin B6 intake and risk of pancreatic cancer: a prospective study of Swedish women and men” by Larsson SC, Giovannucci E, and Wolk A, on page 113.

Largely as a result of the increased control of infectious disease, the 20th century witnessed a remarkable increase in life expectancy.1 At the beginning of the 20th century, life expectancy in the United States was only 47 years; by the end of the century, life expectancy had increased to 78 years. Because cancer rates increase exponentially with age, cancer, which had been rare at the beginning of the 20th century, is now a major cause of death. The age-related increase is separate from the smoking-related cancer epidemic, which also caused an increase in the incidence of many cancers, including pancreatic cancer.

The increasing frequency of cancer led to etiologic research aimed at discovering the cause(s) of cancer. The International Agency for Research on Cancer, founded after World War II, began to collect data on worldwide cancer incidence. Their reports disclosed surprisingly large country-specific differences in cancer frequency leading to the hypothesis that environmental or dietary factors rather than inherited genetic factors were a major cause of many cancers.2

The diet–cancer hypothesis seemed especially attractive because of international differences in eating habits. Beginning in the 1950s, many groups sought proof of a link between diet and cancer. Initially, investigators searched for evidence that major dietary factors, such as the fat content of the diet, might increase the risk of cancer; recently, the emphasis has been on dietary components that might lower the risk of cancer. The field has been attractive to researchers and since 1950 over 21,000 articles have been published on diet and cancer. Nearly 700 of these reports specifically mention pancreatic cancer (Figure 1).

  • View full-size image.
  • Figure 1. 

    Publication rate (by decade) for articles on diet and cancer per 10 million Medline publications: 1950–2006. The findings fit a Gompertz growth curve: slow start, then a rapid increase in the 1970s and 1980s, followed by a recent decrease in publication rate.

In this issue of Gastroenterology, Larsson et al present the results of a large cohort study of Swedish males and females that investigates the relationship between dietary methionine and pancreatic cancer. Methionine is an essential sulfur-containing amino acid widely available from dietary sources such as meat or fish, as well as from legumes and other foodstuffs. The main study finding is that methionine protects against pancreatic cancer. Methionine levels were estimated from dietary surveys carried out at the beginning of the study. Although it appears unlikely that few if any of the subjects were deficient in methionine, the authors found that after a mean follow-up period of 7.2 years, the risk of pancreatic cancer was inversely associated with the estimated initial levels of methionine; for those persons with the highest estimated methionine intake, the adjusted risk of pancreatic cancer was less than half the risk found in persons with the lowest intake. Furthermore, the reduction in risk correlated strongly with increasing levels of methionine (trend statistic ≤ 0.0005). In a subgroup analysis, the authors found that the risk reduction was highly significant in never smokers (hazard ratio, 0.15; 95% confidence interval, 0.05–0.52). But similar to results from another cohort study, methionine consumption was not significantly associated with pancreatic cancer risk in smokers.3

What do these findings mean? The results could be important because pancreatic cancer, now the 4th most common cause of cancer mortality in the United States, has an extremely high mortality rate. Although we do know certain risk factors such as smoking, inherited genetic disorders, and predisposing diseases including diabetes and pancreatitis, there are few known preventive measures to reduce the risk of this lethal cancer. The findings of this study imply that the persons with higher estimated levels of a single amino acid have a significant reduction in the risk of pancreatic cancer compared with persons with lower levels.

The study has several strengths. Although not a randomized, controlled intervention trial, cohort studies such as this one are much stronger than case-control studies because exposure data (in this report, baseline methionine levels estimated from initial dietary surveys) is ascertained before the development of cancer, thus minimizing the possibility of differential recall bias by persons who do or do not develop cancer.

Another strength is that the findings are biologically plausible. Lower methionine levels could lead to hypomethylation and DNA hypomethylation is a frequent event in various types of cancer. Many genes that are over expressed in pancreatic cancer are found to be hypomethylated.4 Also, as the authors point out, there is some evidence that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may alter DNA methylation, thereby increasing the risk of pancreatic cancer.5, 6

In addition to methionine, the focus of this investigation, several other ingested substances can alter DNA methylation and are involved in one-carbon metabolism. These substances include alcohol, folate, choline, vitamins B12 and B6, with folate playing a key role.7, 8 Alcohol consumption may be important because it can potentially interfere with folate metabolism.9 However, in this cohort, alcohol consumption was low.

Some reports, including one from the authors of this report, have found that folate, another methyl donor, is protective against pancreatic cancer.10 Although a previous report based on 2 large cohort studies failed to find a significant protective benefit from dietary folate in pancreatic cancer,11 a recent meta-analysis of 5 published studies (1 case-control and 4 cohort studies) by Larsson et al detected a reduction of nearly 50% (95% confidence limits, 0.35–0.67) in pancreatic cancer risk for persons in the highest consumption category compared with persons in the lowest category.12 Thus, there is evidence that dietary folate—a good source for methyl groups—can reduce the risk of pancreatic cancer. This finding supports the concept that methionine might also protect against pancreatic cancer.

What are the weaknesses of this study? Looking at the impact of a single substance such as methionine may be too simplistic because the metabolic breakdown of ingested food yields a complex mixture of hundreds of substances. Indeed, Larsson et al found that the risk of pancreatic cancer in persons with the highest levels of both folate and methionine was only one third the observed risk for patients with the lowest levels of these 2 substances. This finding suggests that the combined beneficial effects of several potential methyl donors may be greater than that of any single component. But if so, then why did the current study fail to demonstrate any protective benefit from increased dietary vitamin B6—a potential donor source for methyl groups?

Another potential weakness relates to timing of dietary measures: the estimates for methionine levels were obtained during adulthood from 1996 consumption data, but they might represent dietary intake in any earlier period of life where dietary intake correlated with the 1996 data. Therefore, we cannot be sure that dietary modification or dietary supplementation in adults will effectively reduce the risk of pancreatic cancer. This may explain why so many reports of dietary intervention studies conducted in middle-aged adults have proved disappointing.

A common problem in many epidemiologic studies is residual confounding. Even though the authors adjusted for many pancreatic cancer risk factors, there is still the possibility that the apparent protective function of methionine is related to confounding by another dietary or nondietary protective factor.

There is also the multiple end-point problem; in addition to methionine, there are hundreds of dietary components that could have been examined and multiple end-points increase the likelihood of the results being due to chance. We need confirmatory reports before concluding that methionine prevents pancreatic cancer.

This report focuses on the beneficial impact of methionine on pancreatic cancer. Could higher levels of methionine lead to increased morbidity or even increased mortality from nonpancreatic disease? Within the body methionine is converted to homocysteine, which has been linked to cardiovascular disease. Do patients with high methionine levels who are in the lowest risk group for pancreatic cancer have an increased risk for cardiovascular disease? Protein is a rich source for methionine; one report suggests that high-protein diets induce postprandial elevations of homocysteine.13 In addition, large doses of methionine have exacerbated psychotic symptoms in schizophrenic patients.14 A final concern is that limited experimental and human evidence suggests that methionine might actually increase the risk of certain cancers, such as gastric cancer.15, 16

This paper provides valuable information about a dietary component that might reduce the risk of pancreatic cancer. Before suggesting that our patients increase their intake of methionine, we need substantial additional data concerning efficacy and safety issues. Only after digesting the cumulative evidence can we offer a public health recommendation. Meanwhile, we can recommend other measures such as avoiding smoking, drinking alcohol in moderation, maintaining a normal body weight, and consuming a well-balanced diet with a variety of foodstuffs.

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References 

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  2. Higginson J. Cancer and environment: Higginson speaks out. Science. 1979;205:1363–13641366
  3. Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol. 2001;153:680–687
  4. Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA, et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 2003;63:4158–4166
  5. Li D, Ahmed M, Li Y, Jiao L, Chou TH, Wolff RA, et al. 5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1470–1476
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  13. Verhoef P, van Vliet T, Olthof MR, Katan MB. A high-protein diet increases postprandial but not fasting plasma total homocysteine concentrations: a dietary controlled, crossover trial in healthy volunteers. Am J Clin Nutr. 2005;82:553–558
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 Supported in part by grants from the C.D. Smithers Foundation and the Italian Association for Cancer Research.

PII: S0016-5085(06)02527-3

doi:10.1053/j.gastro.2006.11.046

Refers to article:

  • Methionine and Vitamin B6 Intake and Risk of Pancreatic Cancer: A Prospective Study of Swedish Women and Men , 18 October 2006

    Susanna C. Larsson, Edward Giovannucci, Alicja Wolk
    Gastroenterology January 2007 (Vol. 132, Issue 1, Pages 113-118)

Gastroenterology
Volume 132, Issue 1 , Pages 441-443, January 2007

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