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. 2009 Oct 3:9:352.
doi: 10.1186/1471-2407-9-352.

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

Milena Casula  1 , Antonio Muggiano, Antonio Cossu, Mario Budroni, Corrado Caracò, Paolo A Ascierto, Elena Pagani, Ignazio Stanganelli, Sergio Canzanella, Mariacristina Sini, Grazia Palomba; Italian Melanoma Intergroup (IMI); Giuseppe Palmieri
Collaborators, Affiliations

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

Milena Casula et al. BMC Cancer. .

Abstract

Background: 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.

Methods: A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16(CDKN2A), 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 p16(CDKN2A) genes.

Results: For melanoma susceptibility, investigations at germline level indicated that p16(CDKN2A) 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, p16(CDKN2A) 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 p16(CDKN2A) silencing).

Conclusion: Our 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.

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Figures

Figure 1
Figure 1
Classification of melanoma cell lines according to alterations in NRAS/BRAF genes and p16CDKN2A/pERK1-2 protein expression. Data regarding occurrence of mutations in BRAF/NRAS genes (mut), down-regulation of p16CDKN2A protein (p16-), and over-expression of phosphorilated ERK1-2 protein (pERK1-2+) are indicated. Exemplificative immunochemical results are shown.
Figure 2
Figure 2
Western blot analysis of M14 and PR-Mel melanoma cell lines. Protein lysates from M14 and PR-Mel cells were resolved by SDS-PAGE gel electrophoresis and transferred to a nylon membrane; the proteins on the membrane were then subjected to immunoblot analysis with antibodies against ERK1-2/pERK1-2 proteins.
See this image and copyright information in PMC

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