title: Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome.
abstract: It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation. We wanted to determine the prevalence of germline MLH1 promoter hypermethylation and of germline and somatic MSH2 promoter hypermethylation in a large group of Lynch syndrome-suspected patients. From a group of 331 Lynch Syndrome-suspected patients we selected cases, who had no germline MLH1, MSH2, or MSH6 mutation and whose tumors showed loss of MLH1 or MSH2, or, if staining was unavailable, had a tumor with microsatellite instability. Methylation assays were performed to test these patients for germline MLH1 and/or MSH2 promoter hypermethylation. Two patients with germline MLH1 promoter hypermethylation and no patients with germline MSH2 promoter hypermethylation were identified. In the subgroup screened for germline MSH2 promoter hypermethylation, we identified 3 patients with somatic MSH2 promoter hypermethylation in their tumors, which was caused by a germline EPCAM deletion. In the group of 331 Lynch Syndrome-suspected patients, the frequencies of germline MLH1 promoter hypermethylation and somatic MSH2 promoter hypermethylation caused by germline EPCAM deletions are 0.6 and 0.9%, respectively. These mutations, therefore, seem to be rather infrequent. However, the contribution of germline MLH1 hypermethylation and EPCAM deletions to the genetically proven Lynch syndrome cases in this cohort is very high. Previously 27 pathogenic mutations were identified; the newly identified mutations now represent 16% of all mutations.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Krista
authors.initials: K
authors.lastname: Kooi
authors.forename: Paul O J
authors.initials: PO
authors.lastname: Jager
authors.forename: Marloes L
authors.initials: ML
authors.lastname: de Groote
authors.forename: Trijnie
authors.initials: T
authors.lastname: Dijkhuizen
authors.forename: Maran J W
authors.initials: MJ
authors.lastname: Olderode-Berends
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein