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.

Castiglia, D., Pagani, E., Alvino, E., Vernole, P., Marra, G., Cannavò, E., et al. (2003). Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma. GENES, CHROMOSOMES & CANCER, 37(2), 165-175 [10.1002/gcc.10193].

Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma

VERNOLE, PATRIZIA;
2003-06-01

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.
giu-2003
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/13 - BIOLOGIA APPLICATA
English
Con Impact Factor ISI
Alleles; dna repair; middle aged; loss of heterozygosity; adenosine triphosphatases; mutation; chromosomes, human, pair 3; neoplasm proteins; female; colonic neoplasms; carrier proteins; dna-binding proteins; humans; melanoma; dna repair enzymes; skin neoplasms; nuclear proteins; rna, messenger; adaptor proteins, signal transducing; base pair mismatch; tumor cells, cultured; chromosome deletion; genetic markers; leg
Castiglia, D., Pagani, E., Alvino, E., Vernole, P., Marra, G., Cannavò, E., et al. (2003). Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma. GENES, CHROMOSOMES & CANCER, 37(2), 165-175 [10.1002/gcc.10193].
Castiglia, D; Pagani, E; Alvino, E; Vernole, P; Marra, G; Cannavò, E; Jiricny, J; Zambruno, G; D'Atri, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/22751
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