Abstract 654: Do epimutations affect MLH1 alone or a broad spectrum of genes to increase the severity of the associated cancer phenotype.

Abstract

Abstract Germline mutations of the DNA mismatch repair genes, MLH1 and MSH2, are the major cause of Lynch syndrome, characterised by a predisposition to the development of microsatellite unstable colorectal, endometrial and additional cancers below 50 years of age. However, approximately one third of cases with a clinical suspicion have no identifiable mismatch repair sequence mutation. In recent years, constitutive epigenetic dysregulation of MLH1, so-called “constitutional epimutation," has been identified in a small proportion of these mutation-negative cases. The mechanism of onset and stochastic intergenerational transmission of this defect remains unknown, but may involve the co-inheritance of a trans-acting factor that causes aberrant epigenetic programming of MLH1, and possibly additional loci, in the germline or early embryo. The aim of this work is to determine if constitutional MLH1 epimutations occur in a focal manner, or in the context of a more generalised epigenomic mechanism that may exacerbate the cancer phenotype. Using the Illumina HumanMethylation450k BeadChip we studied 6 confirmed carriers of an MLH1 epimutation and 6 healthy controls matched for age and gender to determine if MLH1 epimutations are accompanied by additional epigenetic defects. Preliminary results have shown that other genes are indeed concomitantly and aberrantly methylated or hypomethylated alongside MLH1 and the methylation status of these genes is currently under validation. The finding of concomitant methylation or hypomethylation of additional loci would provide strong evidence for a defective trans-acting factor as the underlying cause of epimutations and may also contribute to the phenotypic expression of this aetiological mechanism. Citation Format: Amanda G. Silva, Konsta Duesing, Robyn Ward, Megan Hitchins. Do epimutations affect MLH1 alone or a broad spectrum of genes to increase the severity of the associated cancer phenotype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 654. doi:10.1158/1538-7445.AM2013-654