Colorectal cancer microsatellite instability

grantor: University of Toronto'Background'. Colorectal cancer is the third most common cancer in both sexes and the second leading cause of cancer-related deaths in Canada. Microsatellite DNA sequences, common throughout the human genome, are subject to high rates of mutation in approximately 15% of colorectal cancers due to deficiency in DNA mismatch repair. Mutations of the 'Adenomatous Polyposis Coli' ('APC') gene are thought to initiate colorectal neoplasia. The 'APC I1307K' polymorphism, common in the Ashkenazi Jewish population, contains an (A)8 microsatellite repeat. The clinical relevance of mismatch repair deficiency and microsatellite instability in colorectal cancer is incompletely understood, as is the cancer risk of the 'APC I1307K' polymorphism. 'Methods'. Tumors from a population-based series of 607 young patients with colorectal cancer from were screened for microsatellite instability and 476 Ashkenazi Jewish patients with colorectal neoplasms were screened for the 'APC I1307K ' polymorphism. 'Results'. High-frequency microsatellite instability (MSI-H) was observed in 17% of the cancers from the population-based series. Patients with MSI-H colorectal cancers were found to have significantly better survival in multivariate analysis and MSI-H cancers were less likely to metastasize after controlling for the extent of tumor invasion. The ' APC I1307K' polymorphism was present in more than 10% of Ashkenazi Jewish patients with colorectal neoplasia. The (A)8 microsatellite sequence of the 'APC I1307K' polymorphism was subject to a very high rate of somatic mutation by a mechanism apparently not related to mismatch repair deficiency. An additional polymorphism, 'APC E1317Q ', was identified in this series, but did not appear to be associated with a significant risk for colorectal neoplasia. 'Conclusions'. MSI-H is relatively common in colorectal cancers and defines a distinct disease subtype with an improved survival and a decreased risk of metastasis. The ' APC I1307K' polymorphism is a risk factor for colorectal neoplasia due to somatic mutation of the (A)8 polymorphic microsatellite sequence.Ph.D