title: Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility.
abstract: Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling.
authors.affiliation: Oncologie et Génétique Moléculaires, Service de Biochimie et Biologie Moléculaire HMNO, CHRU de Lille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Crépin
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Dieu
authors.forename: Sophie
authors.initials: S
authors.lastname: Lejeune
authors.forename: Fabienne
authors.initials: F
authors.lastname: Escande
authors.forename: Denis
authors.initials: D
authors.lastname: Boidin
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.forename: Gilles
authors.initials: G
authors.lastname: Morin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein