Abstract for presentation at 11th International Congress of Human Genetics

Colorectal carcinogenesis involves multiple genetic alternations and environmental exposures that span a long period of time. Identification of specific genetic signatures may allow early detection and surveillance of individuals, who are at risk of developing colorectal cancer. Among the extensively studied molecular abnormalities in colon carcinogenesis is the elevated expression of the enzyme cyclooxygenase-2 (Cox-2), which is a key enzyme in the arachidonic acid signaling pathway.
Genetic polymorphisms have been implicated in susceptibility to cancers as well as in therapeutic response. Analysis of potentially functional polymorphisms in candidate genes has recently emerged as a powerful approach in deciphering the complex relationship between genotype and phenotype. We therefore sought to examine the influence of genetic variants of Cox-2 on adenoma risk in Causcasians and African Americans. We used an exhaustive approach of genotyping nine haplotype-tagging SNPs (ht SNPs) in 772 cases of advanced adenomas and 777 age-matched controls in Caucasians from the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. A total of 13 htSNPs in Cox-2 were genotyped in 72 cases of advanced adenomas and 146 polyp-free controls. All ht SNPs, except for one, were from the regulatory regions distributed over the entire gene including the promotor, intronic, and 3’ untranslated region (UTR). Protective or risk associations were noted with specific genetic variants of Cox-2 in Caucasian and African-American populations. In particular, an intronic variant of Cox-2, intron 5-5229, had a protective effect in Caucasians, whereas the same allele was associated with an increased risk of adenoma development in African-Americans. Our analysis also underscored the significance of the overall allelic architecture of Cox-2 and gene-environment interactions as important determinants for risk assessment and response to chemoprevention/intervention agents. Our results, if confirmed in larger sample sizes, would be helpful in identifying individuals at increased risk for developing colorectal cancer and potentially avoiding harmful effects of aspirin by controlling drug exposure based upon genetic make-up.