Abstract
BackgroundSeveral genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease.MethodsA large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16CDKN2A, BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16CDKN2A genes.ResultsFor melanoma susceptibility, investigations at germline level indicated that p16CDKN2A was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16CDKN2A gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16CDKN2A silencing).ConclusionOur findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.
Highlights
Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma
Predisposing mutations in melanoma Genomic DNA from 301 melanoma patients with ascertained Sardinian origin and 545 melanoma cases originating from non-Sardinian southern Italian regions was screened for germline mutations of p16CDKN2A, the main melanoma susceptibility gene
polymerase chain reaction (PCR) products corresponding to the coding exons and intron-exon junctions were analyzed for mutations as described in Methods
Summary
Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. Both incidence and mortality rates of melanoma have been increasing over the past decades [1]. Baseline melanoma incidences have been found to vary according to the population's origin: Australia, the United States, and Sweden present a higher baseline incidence than Europe (except Sweden) [3,4]. Considering the European population, there is a gradient of melanoma incidence moving from northern countries (where incidence is higher) to southern countries [5]. In Italy, different incidence rates of melanoma between the northern and southern parts of the country (standardized rates per year per 100.000 inhabitants: 10.5-13.5 in North Italy versus 3.5-4.5 in South Italy) have been reported [5]. Environmental and, mostly, genetic factors have been demonstrated to participate in susceptibility and pathogenesis of human melanoma. An intermittent exposure to ultraviolet radiation, especially in combination with endogenous factors like skin type and number of nevi, is the most commonly involved environmental factor [6,7,8,9]
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