FOLATE PATHWAY POLYMORPHISMS AND PANCREATIC CANCER RISK

Summary

Principal Investigator: Michael G Goggins
Abstract: Pancreatic cancer is the fifth leading cause of cancer death in the USA. Currently, there is no effective screening test for asymptomatic individuals and the vast majority of patients with pancreatic cancer present with advanced incurable disease. To reduce the burden of pancreatic cancer, we need to detect early pancreatic cancers and define those at risk of developing the disease. This is particularly true of individuals with a family history of pancreatic cancer, with germline mutations of BRCA2, with germline mutations in p16, or with familial pancreatitis who have lifetime risks of developing pancreatic cancer ranging from 5-40%. Identifying modifiable risk factors may help reduce the burden of this deadly disease. Low folate status has been shown to increase the risk of several cancers and genetic polymorphisms in the folate pathway alter this risk. Since pancreatic cancer leads to cachexia, weight loss and maldigestion, identifying nutrient risk factors for pancreatic cancer utilizing a case-control design has limitations. Studies of genetic polymorphisms that impair folate metabolism and mirror environmental exposures can predict the significance of folate status on pancreatic cancer risk. Several studies have demonstrated that common and functionally significant polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR) and methionine synthase are associated with a reduced risk of several cancers. MTHFR impairment preferentially maintains folates as 5, 10 methylene THF, thereby maintaining optimal thymidine production, at the expense of less methylTHF, needed for DNA methylation. If DNA hypomethylation is an important predisposing factor to cancer formation, polymorphisms in the folate pathway that impair the formation of SAM such as methionine synthase (MS) should increase cancer risk. We hypothesize that defective MTHFR and MS function arising from genetic polymorphisms will protect against pancreatic cancer. If true, it would suggest that thymidine incorporation is more important for cancer protection than reduced methyl group availability for DNA methylation. Carriers of polymorphisms in MTHFR and MS may also be more likely to harbor DNA hypomethylation in their pancreatic cancers of individuals. We will determine i) the prevalence of polymorphisms in the folate pathway (the 677C>T, 1298A>C MTHFR and the 2756A>G MS polymorphisms) in 350 pancreatic cancer cases and in 350 non-cancer controls and ii) determine if DNA hypomethylation in pancreatic cancer xenograft DNA is related its' MTHFR and MS status.
Funding Period: 2001-08-22 - 2003-06-30
more information: NIH RePORT