Colorectal cancer epidemiology: Genes, environment, and history.

Although colorectal cancer (CRC) is the third most common cancer in the United States, 75% of CRC occurs in individuals with no known risk factors. In this dissertation, I explore the importance of ancestral heritage, family history of cancer, BRCA mutations, APC D1822V, APC I1307K, and dietary fat on the risk of CRC development, using data from the Molecular Epidemiology of Colorectal Cancer study, a population-based matched case-control study of CRC in Israel. To investigate BRCA founder mutations common in the Ashkenazim and family history of breast cancer as potential CRC risk factors, we genotyped 901 Ashkenazi cases and 965 Ashkenazi controls for BRCA1 185delAG and 5382insC, and BRCA2 6174delT. BRCA founder mutations were associated with a non-significantly increased risk of CRC (odds ratio [OR] = 1.44, 95% confidence interval [CI] 0.77--2.72). A family history of breast cancer was also associated with a non-significantly increased CRC risk (OR = 1.28, 95% CI 0.88--1.87). APC D1822V, a common polymorphism, has been suggested to reduce CRC risk in individuals consuming a low fat diet. We genotyped 876 cases and 987 controls for D1822V. Compared to homozygous wild type individuals with a high fat diet, homozygous variant individuals consuming a low fat diet did not have a decreased risk of CRC (OR = 1.03, 95% CI 0.22--4.74). The D1822V polymorphism did not affect APC expression, nor was it predicted to alter function, suggesting that D1822V is unlikely to influence CRC risk. The APC I1307K allele, found in 6% of the Ashkenazim and 1--2% of the Sephardim, confers an increased CRC risk. To understand the ethnic distribution of I1307K, we examined its allelic age by genotyping 83 matched pairs, in which one or both of the pair carried I1307K, at five markers. The ancestor of modern I1307K alleles existed approximately 2200--2950 years ago, circa the beginning of the Jewish Diasporas, explaining the presence of I1307K in non-Ashkenazi populations. Furthermore, our data do not indicate that selection operated at I1307K, suggesting that the high frequency of disease susceptibility alleles, including I1307K, in the Ashkenazim is due to genetic drift, not selection.PhDBiological SciencesHealth and Environmental SciencesMolecular biologyOncologyPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124902/2/3163900.pd