''Second hit'' in sebaceous tumors from muir-torre patients with germline mutations in MSH2: Allele loss is not the preferred mode of inactivation

Muir-Torre syndrome is an autosomal-dominant inherited disorder predisposin g to both sebaceous skin tumors and internal neoplasms. In a significant pr oportion of Muir-Torre syndrome patients skin tumors exhibit microsatellite instability as a hallmark of hereditary nonpolyposis colorectal cancer. Mo st individuals predisposed to hereditary nonpolyposis colorectal cancer har bor a germline mutation in the DNA mismatch repair genes MSH2 or MLH1. In M uir-Torre syndrome the vast majority of germline mutations have been identi fied in MSH2. Microsatellite instability in tumor tissue develops after som atic inactivation of the corresponding second mismatch repair allele (''sec ond hit''). So far, the mechanisms of somatic inactivation of the second al lele in microsatellite instability positive tumors from patients with known mismatch repair germline mutations are not well understood. We examined wh ether allele loss (loss of heterozygosity) is a frequent mechanism for inac tivation of the second MSH2 allele in a sample of nine microsatellite insta bility positive skin tumors from eight unrelated Muir-Torre patients with k nown MSH2 germline mutations. Loss of heterozygosity was determined using m icrosatellite markers or heteroduplex analysis, respectively. Only one of t he nine skin tumors exhibited loss of heterozygosity at the MSH2 locus. Thu s, we could show in a sample of sebaceous tumors from patients with genetic ally proven Muir-Torre syndrome that loss of heterozygosity most probably i s not the preferred mode of somatic inactivation of the second MSH2 allele.