Purpose: The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. Methods: Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. Results: When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. Conclusions: This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
Bibliographical noteFunding Information:
The gene-level results using the Adaptive Rank Truncated Product approach, of the 37 genes in a total of 1,407 pancreatic cancer cases and 1,463 controls. For each SNP, the logistic regression analysis used adjustment for age in 10-year categories, sex, study, five principal components of population stratification. Adjustment for multiple comparisons was done using an FDR correction for the cohort and combined stage, and using a Bonferroni correction for the case– control stage a Gene neighborhood within 20 kb upstream and 10 kb downstream of SNP b Chromosome and NCBI Human genome Build 36 location c Subset: cohort, cohort studies; replication, case–control, case–control studies; combined, all studies Acknowledgments This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. This study has been funded by the World Cancer Research Fund (Grant No. 2008/51 to PV). For full acknowledgments, please see electronic supplementary material.
- One-carbon metabolism
- Pancreatic cancer