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Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome
Author(s) -
Rahner N,
Friedrichs N,
Steinke V,
Aretz S,
Friedl W,
Buettner R,
Mangold E,
Propping P,
Walldorf C
Publication year - 2008
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2263
Subject(s) - mlh1 , germline mutation , lynch syndrome , msh2 , biology , microsatellite instability , germline , genetics , dna mismatch repair , dna methylation , cancer research , mutation , gene , dna repair , microsatellite , gene expression , allele
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 co mbined b isulphite r estriction a nalysis (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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.