Abstract 417: DNA methylation changes in Lynch syndrome and FAP-associated colorectal tumorigenesis

Abstract

Abstract Colorectal cancer (CRC) develops via multiple steps which involve genetic changes, such as mutations in growth-regulatory genes, and epigenetic alterations, such as CpG island hypermethylation. These changes accumulate over time in the normal tissue, for example due to many environmental factors such as diet, and may result in pre-cancerous field defects. Genes having high level of methylation in peritumoral tissues could be used as biomarkers for colorectal carcinogenesis. The most common familial cancer susceptibility syndromes are familial adenomatous polyposis (FAP), caused by inherited mutations in the APC tumor suppressor gene, and Lynch syndrome (LS), associated with inherited defects of the DNA mismatch repair (MMR) genes which together with other genetic and epigenetic changes are known to accelerate tumorigenesis. This investigation was designed to define how CpG island methylation of CRC risk genes varies in pre-cancerous and cancerous lesions, adjacent normal mucosa and distinct normal mucosa from genetically predisposed individuals. Colonic mucosa biopsies from different colorectal regions were gathered from 40 Finnish LS mutation carriers and 23 FAP patients during regular surveillance. In addition with normal mucosa biopsies, all adenoma and carcinoma findings from these individuals together with matching normals were gathered and analyzed. Patient information was obtained from the nation-wide registry. CpG island methylation was studied with the methylation-specific multiplex ligation-dependent probe amplification test (MS-MLPA) which detects CpG methylation of selected genes. Immunohistochemistry was used to detect MMR protein expression in neoplastic lesions. Of 16 CRC risk genes tested so far 9 show increased methylation in polyps/adenomas/carcinomas. Mean methylation values increase along with age in both syndromes, with polyps from LS showing the highest proportional increase relative to normal tissues. The results offer new insights to the molecular mechanisms through which DNA methylation can affect colorectal carcinogenesis in LS and FAP mutation carriers. Citation Format: Satu Valo, Sippy Kaur, Ari Ristimäki, Laura Renkonen-Sinisalo, Heikki Järvinen, Jukka-Pekka Mecklin, Minna Nyström, Päivi Peltomäki. DNA methylation changes in Lynch syndrome and FAP-associated colorectal tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 417. doi:10.1158/1538-7445.AM2014-417