Dna Methylation Changes In Lynch Syndrome Associated Colorectal Adenomas And Carcinomas

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAColorectal 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. Lynch syndrome (LS) is one of the most common inherited cancer susceptibility syndromes and is associated with inherited defects of the DNA mismatch repair (MMR) genes, which together with other genetic and epigenetic changes are known to accelerate tumorigenesis. In this investigation we explored the timing of CpG island methylation changes in the course of transformation of normal colonic mucosa to pre-cancerous and cancerous lesions in genetically predisposed individuals.Colorectal neoplastic lesions including low-grade adenomas, high-grade adenomas and carcinomas together with matching normal tissue were gathered from 43 LS mutation carriers enrolled in colonoscopy surveillance. Frequency of CpG island methylator phenotype (CIMP) in different tumor types was analyzed with the methylation-specific multiplex ligation-dependent probe amplification test (MS-MLPA) which detects simultaneously the methylation status of eight CIMP marker genes. Additionally, we analyzed the methylation status of seven selected tumor suppressor genes previously associated with early colon oncogenesis. Immunohistochemistry was used to detect MMR protein expression in neoplastic lesions.We show that the expression of the MMR protein corresponding to the germline mutation decreases along with increasing dysplasia in tumors. Similarly, methylation increases in LS adenomas and carcinomas together with dysplasia grade in comparison to normal colonic mucosa. A proportion of low-grade adenomas could already be classified CIMP positive, and the frequency of CIMP further increased in high-grade adenomas and carcinomas. Our results offer new insights into the molecular mechanisms through which DNA methylation can affect colorectal carcinogenesis in LS mutation carriers.Citation Format: Satu Valo, Sippy Kaur, Ari Ristimaki, Laura Renkonen-Sinisalo, Heikki Jarvinen, Jukka-Pekka Mecklin, Minna Nystrom, Paivi Peltomaki. DNA methylation changes in Lynch syndrome associated colorectal adenomas and carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2015-4766