In this large population-based study, our results suggested that total folate intake was associated with a decreased risk of pancreatic cancer. Higher folate intake from food or from supplements was associated with similar modest lower risk estimates for pancreatic cancer. In addition, an increased risk estimate for pancreatic cancer was observed among those with higher vitamin B12 intake from food. Results from stratified analyses suggested that the inverse association between total folate intake and pancreatic cancer was somewhat stronger among never smokers, those who consumed ≤1 alcoholic drink/day, or those with a high level of food-related methionine intake.
Results have been inconsistent from the few epidemiologic studies that have examined the role of dietary folate and risk of pancreatic cancer [18
]. In the published case-control studies, dietary folate was associated with a reduced risk of pancreatic cancer in the Australian study [18
], whereas no association was observed in the U.S. study [19
]. In contrast, results were somewhat consistent across the several prospective cohort studies [20
], where similar to our findings, a reduced risk of pancreatic cancer was observed with higher folate intake from food alone [20
]. However, results related to total folate intake or folate from supplements were inconsistent across these studies with report of a non-significant increased risk for folate supplement use in Finnish male smokers [20
], no association with total folate or use of folate supplements in the pooled analysis of two U.S. studies [21
], and an inverse association with total folate, but no association with use of folate supplements in the pooled analyses of two Swedish studies [22
]. Interestingly, results from analyses of serum or plasma folate levels in participants from several of these cohort studies were somewhat consistent with the results for dietary measures of folate. An inverse dose-response between serum folate and pancreatic cancer among the cohort of male smokers in Finland [23
] was consistent with the food-related folate results [20
], whereas a suggestive inverse trend between plasma folate levels and pancreatic cancer among participants in four large U.S. cohort studies was limited to nonusers of multivitamins [24
], similar to the dietary results from two of these four studies [21
Alcohol consumption and cigarette smoking can affect folate absorption and metabolism [26
], and thus could increase the requirement for folate intake. Alcohol consumption has been shown to modify the association between folate and risk of colon [41
] and breast cancer [42
]. Similar to several earlier pancreatic cancer studies [20
], we found no evidence of an overall interaction between alcohol consumption or cigarette smoking and folate intake in relation to pancreatic cancer risk. However, results from our stratified analyses suggested that the reduced risk may be somewhat stronger in never smokers or those who consumed an average of ≤1 alcoholic drink per day. It is possible that the increased risk associated with smoking or drinking overrides the risk reduction related to higher folate intake in these subgroups. Given that the small number of current smokers or heavy drinkers in our study limited our ability to further examine the intriguing results from our stratified analyses, further investigation is warranted in larger pooled studies.
Overall, the few studies that have examined vitamin B6 and pancreatic cancer risk [18
] do not provide support of an association. Consistent with our null findings, two cohort studies [20
] reported no association between vitamin B6 and pancreatic cancer, whereas results from a small case-control study showed an inverse association [18
]. The one study that evaluated plasma levels of vitamin B6 and pancreatic cancer risk showed a somewhat inverse association only among nonusers of multivitamins [24
Some support for our result showing a modest increased risk of pancreatic cancer with higher vitamin B12 intake from food is provided by other studies of pancreatic cancer [18
] and studies of other cancers including prostate [43
], esophageal and gastric cancer [45
]. Vitamin B12 intake from food is derived almost exclusively from animal sources, such as meat, milk, and eggs. It is possible that vitamin B12 may be a proxy for other factors or nutrients or a measure of intake of these foods. However, positive associations were not attenuated with additional adjustment of intake of meat, eggs, dairy products, total or saturated fat. The observed increased risk also may be a result of unmeasured confounding. For example, heterocyclic amines formed in meats that are cooked at high temperatures have been associated with increased pancreatic cancer risk [46
]. However, we were unable to determine the effect of cooking methods on the association with vitamin B12 as cooking method data were not collected in our study. These associations require further examination in large pooled studies that can assess vitamin B12 from multiple sources and evaluate other potential confounders and effect modifiers in detail such as the effect of cooking methods.
In a Medline search of articles published in English, we found three cohort studies that had evaluated the association between pancreatic cancer and methionine intake [20
]. Consistent with our results, two of these studies reported no association with methionine intake [20
], whereas a pooled analysis of two Swedish studies showed a strong decreasing trend in risk (Ptrend
]. Methionine is critical in the production of S
-adenosylmethionine, an important methyl donor for DNA methylation. Folate plays an integral role in the remethylation of homocysteine to methionine. If methionine levels are low, more folate may be needed as methyltetrahydrofolate to form methionine. Therefore, it is plausible that methionine levels could modify an association between folate and pancreatic cancer. Our results and those from two U.S. cohort studies [21
] found no overall evidence of a significant interaction between folate and methionine intake related to pancreatic cancer. In contrast, results from the pooled Swedish cohorts [25
] showed that those with high intake of folate and high intake of methionine had the greatest reduced risk of pancreatic cancer. Interestingly, although there was no overall interaction between methionine and folate intake in our study population, the results from our folate analyses stratified by low and high methionine intake supported the results reported in the Swedish cohort study. Further investigation in large pooled studies is needed to elucidate these findings and to assess whether methionine alters the association between folate intake and pancreatic cancer.
Overall, the results from our and other published studies suggest that high folate intake may be associated with a decreased risk of pancreatic cancer. However, despite some similarities across studies, the underlying differences in study designs, study populations, and classification of folate and other nutrients make a summary interpretation of the literature on folate and B vitamins difficult. Results from two of the three cohort studies may not be generalizable to the general population given that one study was conducted among a cohort of Finnish male smokers and the other among cohorts of U.S. nurses and health professionals [20
]. In addition, results from most studies were based on a small number of cases (typically < 200 cases). Differences in dietary habits and patterns across study populations also were likely to have contributed to observed discrepant results e.g. the Swedish study population had on average a lower rate of folate supplement use and lower folate status than those of the published U.S. populations [22
]. These differences suggest that strong associations may be detectable only in populations that include a large number of participants with low folate status (e.g. <200ug/day, the cutpoint for the reference group used in the Swedish cohorts). Thus, based on the current published literature, large and well-designed studies are needed to clarify the role that folate and other B-vitamins (from food and from supplements) play in risk of pancreatic cancer.
This large population-based study included 532 pancreatic cancer cases, the largest number of cases in the published studies that have examined the effect of methyl-group nutrients on pancreatic cancer. Rapid case ascertainment with a goal to identify eligible cases within one month of diagnosis was used to reduce selection bias and to diminish the effects of the short survival and high mortality rates on patient recruitment. We also had a low refusal rate of 8% among the cases. However, given the high fatality of pancreatic cancer, if patient participants were healthier and therefore more likely to have better diets with resultant higher levels of nutrient intake than not interviewed patients, then our results may be biased toward the null. Extensive data were collected during in-person interviews by trained interviewers, eliminating information bias associated with use of proxy data and enabling us to consider numerous potential confounders and effect modifiers in our analyses. To help minimize the effects of reverse causation and recall bias, participants were asked to report their usual diet a year prior to diagnosis (cases) or interview (controls) and were provided with food models for serving sizes, and the FFQ also was administered in a consistent manner by a trained interviewer. In addition, we collected data about dietary changes over the past ten years and found no evidence that cases were more likely to change their diet than were controls [7
]. However, when answering specific dietary questions, it is possible that cases and controls who had experienced dietary changes may have differentially reported these changes. If cases were more likely to have reported decreased consumption of some foods then our results may have been biased away from the null, whereas if dietary changes were subtle and gradual among cases due to their disease then dietary recall may not accurately have reflected a change and our results may be biased toward the null.
In conclusion, our results have provided evidence that high folate intake is associated with a decreased risk of pancreatic cancer although there was no evidence of an association with intake of other nutrients important in methyl-group metabolism such as vitamin B6 and methionine. The increased risk estimate for pancreatic cancer associated with higher intake of vitamin B12 from food requires confirmation and additional investigation in future studies.