Abstract for presentation at 11th International Congress of Human Genetics

Polymorphisms in the Mismatch Repair Genes and Colorectal Cancer Risk in Canadian population

  • Bharati Bapat, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
  • Mr Miralem Mrkonjic, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
  • Miss Stavroula Raptis, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
  • Dr Julia Knight, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
  • Dr Steve Gallinger, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
  • Dr Banfield Younghusband, Memorial University of Newfoundland, Canada
  • Dr Roger Green, Memorial University of Newfoundland, Canada
  • Dr John McLaughlin, Samuel Lunenfled Research Institute, Mount Sinai Hospital, University of Toronto, Canada

    • Colorectal cancer (CRC) arises due to interactions between genetic and environmental risk factors. Defects in mismatch-repair (MMR) genes cause HNPCC, an inherited form of CRC, and also result in genome-wide microsatellite instability (MSI) in colon tumours. A number of SNPs in MMR genes have been identified, but little is known about their significance in CRC. We hypothesized that some MMR SNPs affect functional variation in MMR and contribute to CRC susceptibility, and the specific contribution of MMR SNPs to the development of CRC may vary by population. Specifically, a genetically isolated founder population with a high incidence of CRC, such as Newfoundland, may have a limited set of SNPs, which will have a greater population attributable risk compared to a more diverse population such as Ontario. We examined the association between candidate SNPs in MLH1 (promoter -93 G>A, I219V, IVS14-19 A>G) and MSH2 (promoter -118 T>C, G322D, IVS12-6 T>C) genes and family history of CRC, MSI status, age of onset and tumour location and stage, among 990 cases and 1160 controls from Ontario, and 500 cases and 350 controls from Newfoundland. A significant association of MMR SNPs with the overall incidence of CRC was not observed in either population, and variant allele frequencies were comparable among Ontario and Newfoundland populations. However, MLH1 –93 A allele carriers were significantly associated with family risk (p<0.01), MSI-High tumours (p<0.01) and TNM stage (p<0.05) in Ontario CRC patients and tumour MSI-high status (p<0.02) in Newfoundland CRC patients. Additionally, MSH2 –118 C allele carriers were associated with family risk (p<0.03), MSI-High tumours (p=0.05) in Ontario CRC patients and more commonly occurred among male CRC patients (p<0.01) in both Ontario and Newfoundland cases. Functional analyses of these MMR promoter SNPs are currently in progress. These results demonstrate that certain MMR SNPs contribute to CRC risk among subsets of CRC patients.

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