title: Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome.
abstract: Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome.
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany. n.rahner@uni-bonn.de
authors.forename: N
authors.initials: N
authors.lastname: Rahner
authors.forename: N
authors.initials: N
authors.lastname: Friedrichs
authors.forename: V
authors.initials: V
authors.lastname: Steinke
authors.forename: S
authors.initials: S
authors.lastname: Aretz
authors.forename: W
authors.initials: W
authors.lastname: Friedl
authors.forename: R
authors.initials: R
authors.lastname: Buettner
authors.forename: E
authors.initials: E
authors.lastname: Mangold
authors.forename: P
authors.initials: P
authors.lastname: Propping
authors.forename: C
authors.initials: C
authors.lastname: Walldorf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1