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Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome
Author(s) -
Niessen Renée C.,
Hofstra Robert M. W.,
Westers Helga,
Ligtenberg Marjolijn J. L.,
Kooi Krista,
Jager Paul O. J.,
de Groote Marloes L.,
Dijkhuizen Trijnie,
OlderodeBerends Maran J. W.,
Hollema Harry,
Kleibeuker Jan H.,
Sijmons Rolf H.
Publication year - 2009
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20678
Subject(s) - lynch syndrome , msh2 , mlh1 , germline , germline mutation , cancer research , biology , msh6 , microsatellite instability , genetics , microbiology and biotechnology , mutation , dna mismatch repair , cancer , colorectal cancer , gene , microsatellite , allele
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. © 2009 Wiley‐Liss, Inc.