Missense Polymorphisms in the Adenomatous Polyposis Coli Gene and Colorectal Cancer Risk

Abstract

Purpose: Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms ofAPCmay confer a weaker risk for colorectal cancer. Methods: We sequenced the entire open reading frame of theAPCgene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects. Results: GermlineAPCor mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missenseAPCgene alterations (S130G, E1317Q, D1822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APCY94X, biallelicMYHY165C and heterozygousMYHG382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missenseAPCalterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130G = 3.1 (0.29-32.25), E1317Q = 1.08 (0.59-2.74), G2502S = 1 (0.65-1.63), D1822V (heterozygous) = 0.79 (0.64-0.98), D1822V (homozygous) = 0.82 (0.63-1.27). Conclusions: Germline missenseAPCalterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.