title: Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma.
abstract: Inactivation of mismatch repair (MMR) genes has been linked to the hereditary nonpolyposis colon cancer syndrome and to a subset of sporadic cancers. A phenotypic characteristic of tumors with defective MMR is microsatellite instability (MSI). Although MSI has been reported in a proportion of cutaneous melanomas, inactivation of MMR genes in this tumor type has not been detected thus far. We recently described a human melanoma cell line, PR-Mel, and a cutaneous metastasis from the same patient, which displayed a MMR defect, and showed high MSI. Here we report that in the PR-Mel cell line both MLH1 alleles are somatically inactivated. One allele is lost through a chromosomal deletion of the region 3p21-24, whereas the remaining allele harbors a G --> A transition at position -1 of the acceptor splice site of intron 15, leading to the in-frame skipping of exon 16. The primary melanoma of the PR patient shows loss of heterozygosity at the BAT21 microsatellite marker, located in the MLH1 gene, and does not express the MLH1 and PMS2 proteins. Moreover, it harbors the same mutation detected in the PR-Mel cells. These results demonstrate that biallelic inactivation of MLH1 had occurred in the primary melanoma of the PR patient and suggest that disruption of MMR might have had a role in the development of the melanoma. This is the first report in which genetic defects leading to disruption of MMR function in a human melanoma have been identified.
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
authors.forename: Elena
authors.initials: E
authors.lastname: Pagani
authors.forename: Ester
authors.initials: E
authors.lastname: Alvino
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vernole
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.forename: Elda
authors.initials: E
authors.lastname: Cannavò
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Atri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics*; D002352:Carrier Proteins; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003110:Colonic Neoplasms / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007866:Leg / Q000473:pathology / Q000601:surgery; D019656:Loss of Heterozygosity / Q000235:genetics; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes