NDLI: Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers

Content Provider	PubMed Central
Author	Nagasaka, Takeshi Rhees, Jennifer Kloor, Matthias Gebert, Johannes Yoshio, Naomoto Boland, C. Richard Goel, Ajay
Abstract	Heritable germline epimutations in MSH2 have been reported in a small number of Lynch Syndrome families which lacked germline mutations in the MSH2 gene. It is not known whether somatic MSH2 methylation occurs in MSH2 mutation-positive Lynch Syndrome subjects or sporadic colorectal cancers (CRCs). Therefore, we determined the methylation status of the MSH2 gene in 268 CRC tissues, including 222 sporadic CRCs and 46 tumors that did not express MSH2. We also looked for microsatellite instability (MSI), germline mutations in the MSH2 and EpCAM genes, somatic mutations in BRAF and KRAS, and the CpG island methylator phenotype (CIMP). We observed that somatic MSH2 hypermethylation was present in 24% (11 of 46) of MSH2-deficient (presumed Lynch Syndrome) tumors, while no evidence for MSH2 methylation existed in sporadic CRCs (MSI and MSS) or normal colonic tissues. Seven of 11 (63%) patients with MSH2 methylation harbored simultaneous pathogenic germline mutations in the MSH2 gene. Germline EpCAM deletions were present in 3 of 4 patients with MSH2 methylation but without pathogenic MSH2 germline mutations. The mean methylation scores at CIMP-related markers were significantly higher in Lynch Syndrome tumors with MSH2 methylation than MSH2-unmethylated CRCs. In conclusion, our data provide evidence for frequent MSH2 hypermethylation in Lynch Syndrome tumors with MSH2 deficiency. MSH2 methylation in this subset of individuals is somatic, and may serve as the ‘second hit’ at the wild type allele. High levels of aberrant methylation at CIMP-related markers in MSH2 methylated tumors raises the possibility that MSH2 is a target susceptible to aberrant methylation in Lynch Syndrome.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-3290
Ending Page	3108
Page Count	11
Starting Page	3098
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	8
Volume Number	70
Language	English
Publisher Date	2010-04-15
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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