Abstract
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.
References
Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21(35):5400–5413
Tibbetts AS, Appling DR (2010) Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr 30:57–81
Liu JJ, Ward RL (2010) Folate and one-carbon metabolism and its impact on aberrant DNA methylation in cancer. Adv Genet 71:79–121
Larsson SC, Orsini N, Wolk A (2010) Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA 303(11):1077–1083
Kim D-H, Smith-Warner SA, Spiegelman D et al (2010) Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control 21(11):1919–1930
Collin SM, Metcalfe C, Refsum H et al (2010) Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 19(6):1632–1642
Larsson SC, Giovannucci E, Wolk A (2007) Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 99(1):64–76
Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10(2):66–88
Baghurst PA, McMichael AJ, Slavotinek AH, Baghurst KI, Boyle P, Walker AM (1991) A case-control study of diet and cancer of the pancreas. Am J Epidemiol 134(2):167–179
Bravi F, Polesel J, Bosetti C et al (2011) Dietary intake of selected micronutrients and the risk of pancreatic cancer: an Italian case-control study. Ann Oncol 22(1):202–206
Gong Z, Holly EA, Bracci PM (2009) Intake of folate, vitamins B6, B12 and methionine and risk of pancreatic cancer in a large population-based case-control study. Cancer Causes Control 20(8):1317–1325
Larsson SC, Håkansson N, Giovannucci E, Wolk A (2006) Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst 98(6):407–413
Oaks BM, Dodd KW, Meinhold CL, Jiao L, Church TR, Stolzenberg-Solomon RZ (2010) Folate intake, post-folic acid grain fortification, and pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 91(2):449–455
Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D (2001) Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol 153(7):680–687
Silverman DT, Swanson CA, Gridley G et al (1998) Dietary and nutritional factors and pancreatic cancer: a case–control study based on direct interviews. J Natl Cancer Inst 90(22):1710–1719
Keszei AP, Verhage BAJ, Heinen MM, Goldbohm RA, van den Brandt PA (2009) Dietary folate and folate vitamers and the risk of pancreatic cancer in the Netherlands cohort study. Cancer Epidemiol Biomarkers Prev 18(6):1785–1791
Larsson SC, Giovannucci E, Wolk A (2006) Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 131(4):1271–1283
Ohnami S, Sato Y, Yoshimura K et al (2008) His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk. Gastroenterology 135(2):477–488
Amundadottir L, Kraft P, Stolzenberg-Solomon RZ et al (2009) Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 41(9):986–990
Diergaarde B, Brand R, Lamb J et al (2010) Pooling-based genome-wide association study implicates gamma-glutamyltransferase 1 (GGT1) gene in pancreatic carcinogenesis. Pancreatology 10(2–3):194–200
Low S-K, Kuchiba A, Zembutsu H et al (2010) Genome-wide association study of pancreatic cancer in Japanese population. PLoS ONE 5(7):e11824
Petersen GM, Amundadottir L, Fuchs CS et al (2010) A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 42(3):224–228
Willis JA, Olson SH, Orlow I et al (2012) A replication study and genome-wide scan of single-nucleotide polymorphisms associated with pancreatic cancer risk and overall survival. Clin Cancer Res 18(14):3942–3951
Wu C, Miao X, Huang L et al (2012) Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet 44(1):62–66
Tanaka T, Scheet P, Giusti B et al (2009) Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet 84(4):477–482
Lange LA, Croteau-Chonka DC, Marvelle AF et al (2010) Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. Hum Mol Genet 19(10):2050–2058
Hazra A, Kraft P, Lazarus R et al (2009) Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet 18(23):4677–4687
Midttun Ø, Hustad S, Ueland PM (2009) Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 23(9):1371–1379
Westfall PH, Young SS (1993) Resampling-based multiple testing: examples and methods for p-value adjustment. Wiley, New York, NY
Yu K, Li Q, Bergen AW et al (2009) Pathway analysis by adaptive combination of P-values. Genet Epidemiol 33(8):700–709
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 57(1):289–300
Chuang S-C, Stolzenberg-Solomon R, Ueland PM et al (2011) A U-shaped relationship between plasma folate and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Eur J Cancer 47(12):1808–1816
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.
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Leenders, M., Bhattacharjee, S., Vineis, P. et al. Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4. Cancer Causes Control 24, 595–602 (2013). https://doi.org/10.1007/s10552-012-0138-0
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DOI: https://doi.org/10.1007/s10552-012-0138-0