Data from Somatic Hypermethylation of <i>MSH2</i> Is a Frequent Event in Lynch Syndrome Colorectal Cancers

Abstract

<div>Abstract<p>Heritable germline epimutations in <i>MSH2</i> have been reported in a few Lynch syndrome families that lacked germline mutations in the <i>MSH2</i> gene. It is not known whether somatic <i>MSH2</i> methylation occurs in <i>MSH2</i> mutation–positive Lynch syndrome subjects or sporadic colorectal cancers (CRC). Therefore, we determined the methylation status of the <i>MSH2</i> 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 <i>MSH2</i> and <i>EpCAM</i> genes, somatic mutations in <i>BRAF</i> and <i>KRAS</i>, and the CpG island methylator phenotype (CIMP). We observed that somatic <i>MSH2</i> hypermethylation was present in 24% (11 of 46) of MSH2-deficient (presumed Lynch syndrome) tumors, whereas no evidence for <i>MSH2</i> methylation existed in sporadic CRCs (MSI and microsatellite stable) or normal colonic tissues. Seven of 11 (63%) patients with <i>MSH2</i> methylation harbored simultaneous pathogenic germline mutations in the <i>MSH2</i> gene. Germline <i>EpCAM</i> deletions were present in three of four patients with <i>MSH2</i> methylation but without pathogenic <i>MSH2</i> germline mutations. The mean methylation scores at CIMP-related markers were significantly higher in Lynch syndrome tumors with <i>MSH2</i> methylation than <i>MSH2</i>-unmethylated CRCs. In conclusion, our data provide evidence for frequent <i>MSH2</i> hypermethylation in Lynch syndrome tumors with MSH2 deficiency. <i>MSH2</i> 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 <i>MSH2</i>-methylated tumors raise the possibility that <i>MSH2</i> is a target susceptible to aberrant methylation in Lynch syndrome. Cancer Res; 70(8); 3098–108. ©2010 AACR.</p></div>