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Screening of additional epigenetics events in Lynch patients carrying MLH1 epimutation

Grant number: 12/01472-0
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 18, 2012
Effective date (End): June 17, 2013
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Carla Rosenberg
Grantee:Amanda Gonçalves dos Santos Silva
Supervisor abroad: Megan P. Hitchins
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : University of New South Wales (UNSW), Australia  
Associated to the scholarship:09/08888-5 - Genomic screening in Li-Fraumeni and Li-Fraumeni like families with unknown causes, BP.PD

Abstract

Germline mutations of the DNA mismatch repair genes, MLH1 and MSH2, are the major cause of Lynch syndrome, characterized by a predisposition to the development of microsatellite unstable colorectal, endometrial and additional cancers below 50 years of age. Mutations of the minor mismatch repair genes MSH6 and PMS2 occur more rarely. However, approximately one third of cases with a clinical suspicion of Lynch syndrome have no identifiable sequence mutation within the mismatch repair genes. In recent years, constitutive epigenetic deregulation of MLH1 and MSH2 has been identified in a proportion of these mutation-negative cases. This type of defect is characterized by promoter methylation and transcriptional silencing of a single allele in normal tissues in the absence of an intragenic sequence mutation. Constitutional MLH1 epimutations confer a high risk of development of Lynch syndrome related cancers. However, patients with this molecular defect have presented with multiple primary carcinomas including cancers that are both atypical or rare in carriers of sequence mutations within the mismatch repair genes, and furthermore, the average age of onset of the first cancer has been younger. We will investigate 24 confirmed carriers of an MLH1 epimutation using genome-wide screening for altered methylation patterns at individual genes, repetitive DNA and for skewed X-inactivation. The key aim of this proposal is to determine if the mechanism by which epimutations arise affects additional genes contemporaneously with MLH1, and if furthermore, whether those genes contribute to the severity of the phenotype in these patients. (AU)