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BMC Cancer
Published in: BMC Cancer 1/2009

Open Access 01-12-2009 | Research article

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

Authors: Milena Casula, Antonio Muggiano, Antonio Cossu, Mario Budroni, Corrado Caracò, Paolo A Ascierto, Elena Pagani, Ignazio Stanganelli, Sergio Canzanella, MariaCristina Sini, Grazia Palomba, Giuseppe Palmieri, The Italian Melanoma Intergroup (IMI)

Published in: BMC Cancer | Issue 1/2009

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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.
Appendix
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Metadata
Title
Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy
Authors
Milena Casula
Antonio Muggiano
Antonio Cossu
Mario Budroni
Corrado Caracò
Paolo A Ascierto
Elena Pagani
Ignazio Stanganelli
Sergio Canzanella
MariaCristina Sini
Grazia Palomba
Giuseppe Palmieri
The Italian Melanoma Intergroup (IMI)
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2009
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-9-352

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