| Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. | |
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MedLine Citation:
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PMID: 20388775 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Heritable germline epimutations in MSH2 have been reported in a few Lynch syndrome families that 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 (CRC). Therefore, we determined the methylation status of the MSH2 gene in 268 CRC tissues, including 222 sporadic CRCs and 46 Lynch syndrome 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, whereas no evidence for MSH2 methylation existed in sporadic CRCs (MSI and microsatellite stable) 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 three of four 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 raise the possibility that MSH2 is a target susceptible to aberrant methylation in Lynch syndrome. |
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Authors:
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Takeshi Nagasaka; Jennifer Rhees; Matthias Kloor; Johannes Gebert; Yoshio Naomoto; C Richard Boland; Ajay Goel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-04-13 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-16 Completed Date: 2010-04-28 Revised Date: 2012-03-30 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3098-108 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas 75246, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cohort Studies Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*, metabolism CpG Islands DNA Methylation* Epigenesis, Genetic Gene Expression Regulation, Neoplastic* Genes, ras Germ-Line Mutation Humans Microsatellite Repeats Models, Genetic MutS Homolog 2 Protein / metabolism* Mutation Phenotype Proto-Oncogene Proteins B-raf / genetics |
| Grant Support | |
ID/Acronym/Agency:
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CA129286/CA/NCI NIH HHS; CA72851/CA/NCI NIH HHS; R01 CA072851-14/CA/NCI NIH HHS; R01 CA129286-02/CA/NCI NIH HHS; R01 CA129286-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 2.7.1.37/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 3.6.1.3/MSH2 protein, human; EC 3.6.1.3/MutS Homolog 2 Protein |
| Comments/Corrections | |
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