Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases

Abstract

Summary Malignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Previous cytogenetic and molecular studies indicated the 9p21 as the chromosomal region involved in MM pathogenesis. In addition to the CDKN genes (p16/CDKN2A, p15/CDKN2B and p19 ARF , frequently inactivated in familial MM), widely reported data suggested the presence within this region of other melanoma susceptibility gene(s). To clearly assess the role of the 9p21 region in sporadic melanoma, we evaluated the presence of microsatellite instability (MSI) and loss of heterozygosity (LOH) in primary tumours as well as in synchronous or asynchronous metastases obtained from the same MM patients, using 9 polymorphic markers from a 17-cM region at 9p21. LOH and MSI were found in 27 (41%) and 11 (17%), respectively, out of 66 primary tumours analysed. In corresponding 58 metastases, MSI was found at higher rate (22; 38%), whereas a quite identical pattern of allelic deletions with 27 (47%) LOH+ cases were observed. Although the CDKN locus was mostly affected by LOH, an additional region of common allelic deletion corresponding to marker D9S171 was also identified. No significant statistical correlation between any 9p21 genetic alteration (LOH, MSI or both) and clinicopathological parameters was observed.

Expression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients

“…There is currently a lack of information to define the exact stage at which LOH, microstallite instability, or CDKN2A promoter methylation occurs. [28][29][30] Indeed, recent studies on somatic mutations and LOH at 9p21 suggested that somatic mutations in sporadic primary melanoma are infrequent and found LOH in thick rather than in thin primary melanomas. 31 Alternatively to LOH, a mechanism involving altered folding of the p16 protein from a mutated allele 32 may explain the mislocalized pattern as the result of impaired passage from the nucleus to cytoplasm.…”

Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma

“…CDKN2A inactivation can result from diVerent genetic events. In 20 to 71% of primary sporadic melanomas loss of heterozygosity (LOH) was reported at one or more polymorphic microsatellite markers on 9p21 (Kumar et al 1999;Cachia et al 2000;Palmieri et al 2000). Hemi-or homozygous deletions of CDKN2A were detected in 27.5% by Southern blot analysis (Flores et al 1996) while monosomy 9 was observed in 36.5% by Xuorescent in situ hybridization (FISH) (Matsuta et al 1997).…”

Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi

“…Approximately 10% of malignant melanoma cases occur in multiplex families, with the CDKN2A locus in 9p21 accounting for susceptibility in 20-57% of all melanoma families [2]. However, remaining cases of familial melanoma do not carry mutations in CDKN2A and additional tumor suppressor genes at 9p21 and elsewhere have been proposed [3]. Large numbers of nevi are the strongest known risk factor for melanoma [4] and in many familial cases susceptibility to melanoma is associated with an excess of nevi.…”