Abstract 3360: Origins of mutations in colorectal cancer

Abstract

Abstract The origins of most human cancers remain unclear. In selected cases, exposure to potent environmental mutagens or familial germ line mutations, which affect tumor suppressor genes or oncogenes, have been identified with specific cancers. Wnt signaling due to mutations in APC is compromised as an early event in 75% of human colorectal cancer (CRC), with truncating nonsense mutations (65%) dominating the mutation spectrum. Because 43% of the nonsense mutations occur at Arg CGA codons, the C→T mutation is attributed to hydrolytic deamination of 5-methylC. The enhanced incidence of colorectal cancer (CRC) associated with the Western diet has been epidemiologically linked to heterocyclic aromatic amines (HAA) produced by high temperature cooking of meat. Analysis of the mutation spectra in CRC indicated that the G→T transversions, which are produced by this class of mutagens were not enriched but were actually lower than what would be statistically anticipated based on random mutations. Moreover, the APC mutation patterns in the U.S.A. vs. China are indistinguishable despite differences in diet. However, dissection of the APC mutation pattern in tumors that arise in the different anatomical regions of the large intestine shows that the nonsense mutation pattern in APC differ in the different regions: there is a statistically significant increase in G→T transversions in the rectum vs. the other regions, albeit, the percent of G→T mutations still remains lower than predicted based on random mutagenesis. Therefore, it appears that HAA's may contribute to the incidence of rectal cancer. Citation Format: Barry Gold. Origins of mutations in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3360.