Microsatellite Instability in Melanocytic Skin Lesions (Benign Nevi, Dysplastic Nevi, and Primary Melanomas along with Their Metastases)

Abstract

Malignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Microsatellite instability (MSI) is caused by deficient DNA mismatch repair, and the subsequent increase of replication errors seems to be associated with tumour progression in different types of cancer. Controversial results have been provided about both frequency and significance of MSI in melanoma. In this study, time of onset and relative incidence of MSI were determined during the progression of melanocytic tumours, starting from benign melanocytic nevi. MSI was studied using nine markers covering a 17-cM distance at chromosome 9p21 (where the CDKN melanoma-susceptibility locus maps) and four additional markers from different chromosomal locations. Tumours were classified as low-frequency (L-MSI+) or high-frequency (H-MSI+) MSI, when one or at least two marker loci (respectively) displayed mutant alleles in tumour DNA compared to corresponding normal tissue DNA. None of the 8 melanocytic nevi showed MSI, whereas moderate frequency of H-MSI was detected in dysplastic nevi (1/11; 9%) and primary melanomas (6/56; 11%). The incidence of MSI was increased in melanoma metastases from the same patients (H-MSI: 9/42; 21%). In contrast to previously reported data showing higher rates of MSI in melanoma, genetic instability seems to be present in a minority of MM lesions. However, our findings are consistent with the hypothesis that MSI may be sequentially induced during malignant evolution, contributing to the progression of a subset of melanocytic tumours. In addition, cytogenetic analysis by fluorescence in situ hybridization at chromosome 9p21 on a subset of primary melanoma tissue sections seems to indicate that a new locus (D9S171) may be involved in MM pathogenesis.