"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 predisposing to both sebaceous skin tumors and internal neoplasms. In a significant proportion of Muir-Torre syndrome patients skin tumors exhibit microsatellite instability as a hallmark of hereditary nonpolyposis colorectal cancer. Most individuals predisposed to hereditary nonpolyposis colorectal cancer harbor a germline mutation in the DNA mismatch repair genes MSH2 or MLH1. In Muir-Torre syndrome the vast majority of germline mutations have been identified in MSH2. Microsatellite instability in tumor tissue develops after somatic inactivation of the corresponding second mismatch repair allele ("second hit"). So far, the mechanisms of somatic inactivation of the second allele in microsatellite instability positive tumors from patients with known mismatch repair germline mutations are not well understood. We examined whether allele loss (loss of heterozygosity) is a frequent mechanism for inactivation of the second MSH2 allele in a sample of nine microsatellite instability positive skin tumors from eight unrelated Muir-Torre patients with known MSH2 germline mutations. Loss of heterozygosity was determined using microsatellite markers or heteroduplex analysis, respectively. Only one of the nine skin tumors exhibited loss of heterozygosity at the MSH2 locus. Thus, we could show in a sample of sebaceous tumors from patients with genetically proven Muir-Torre syndrome that loss of heterozygosity most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.
Department of Dermatology, University of Düsseldorf, Düsseldorf, Germany. rkruse@uni-duesseldorf.de
R
R
Kruse
A
A
Rütten
H R
HR
Hosseiny-Malayeri
M
M
Bisceglia
W
W
Friedl
P
P
Propping
T
T
Ruzicka
E
E
Mangold
D000328:Adult; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D018095:Germ-Line Mutation; D020180:Heteroduplex Analysis; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012626:Sebaceous Gland Neoplasms / Q000235:genetics*; D013577:Syndrome
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein