Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy

• Main Authors: Canzanella Sergio, Stanganelli Ignazio, Pagani Elena, Ascierto Paolo A, Caracò Corrado, Budroni Mario, Cossu Antonio, Muggiano Antonio, Casula Milena, Sini MariaCristina, Palomba Grazia, Palmieri Giuseppe
• Format: Article
• Language: English
• Published: BMC 2009-10-01
• Series: BMC Cancer
• Online Access: http://www.biomedcentral.com/1471-2407/9/352

<p>Abstract</p> <p>Background</p> <p>Several 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.</p> <p>Methods</p> <p>A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in <it>p16</it>^{<it>CDKN</it>2<it>A</it>}, <it>BRCA2</it>, and <it>MC1R </it>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 <it>NRAS</it>, <it>BRAF</it>, and <it>p16</it>^{<it>CDKN</it>2<it>A </it>}genes.</p> <p>Results</p> <p>For melanoma susceptibility, investigations at germline level indicated that <it>p16</it>^{<it>CDKN</it>2<it>A </it>}was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas <it>BRCA2 </it>germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two <it>MC1R </it>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 <it>NRAS </it>and <it>BRAF </it>genes were observed at quite same rate (about two thirds) in cultured and <it>in vivo </it>melanomas (either primary or metastatic lesions). Conversely, <it>p16</it>^{<it>CDKN</it>2<it>A </it>}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 (<it>NRAS</it>/<it>BRAF </it>mutations and <it>p16</it>^{<it>CDKN</it>2<it>A </it>}silencing).</p> <p>Conclusion</p> <p>Our findings further clarified that: <it>a</it>) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; <it>b</it>) multiple molecular events are accumulating during melanomagenesis.</p>