Abstract B35: Genetic and epigenetic alterations in colorectal cancer among atomic bomb survivors

Colon cancer among atomic bomb survivors has been shown at a significantly high excess risk attributed to atomic radiation exposure. In this study, we focused on microsatellite instability (MSI)-related colorectal carcinogenesis and analyzed both epigenetic and genetic alterations of MLH1 and Ras-signaling related genes, as well as CpG island methylator phenotype (CIMP). Study subjects were 35 colorectal cancer cases from the RERF cohort study (Life Span Study). The MSI-high (H) was found in five cases with use of six microsatellite markers, showing a significantly higher median radiation dose than that of microsatellite stable (MSS) and MSI-low (L) cases. All five MSI-H cases carried LOH of MLH1, three of which had methylated MLH1 in the remaining alleles. Two cases with unmethylated MLH1 were found to have point mutations in MLH1, presumably causing truncated protein and splicing abnormality. Of 30 MSS and MSI-L cases, two methylated MLH1 cases were identified, i.e., a total of five methylated MLH1 cases in all study cases, and these five cases showed a higher radiation dose than that of unmethylated cases. Undetected levels of MLH1 protein expression were confirmed with four of the five MSI-High cases. Next, we analyzed the gene alterations (BRAF and K-RAS mutations and RASSF2 methylation) in the Ras-signaling pathway, which is thought to be a preceding event of MLH1 methylation. All five MSI-H cases carried one or two alterations of these Ras-signaling-related genes, and a total of 18 cases were found to have altered Ras-signaling-related genes with a significantly higher radiation dose than that of 17 cases without the alternations. When the study cases were grouped by the numbers (2, 1, and 0) of alternated Ras-signaling-related genes, three groups revealed a remarkably increasing trend in radiation dose with increased numbers of altered genes. Although CIMP status significantly correlated with MLH1 methylation, no association was found with CIMP status and radiation dose. The results obtained thus far suggest that radiation exposure may influence MSI-related epigenetic/genetic alterations in colorectal carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B35.