Author:
Casula Milena,Muggiano Antonio,Cossu Antonio,Budroni Mario,Caracò Corrado,Ascierto Paolo A,Pagani Elena,Stanganelli Ignazio,Canzanella Sergio,Sini MariaCristina,Palomba Grazia,Palmieri Giuseppe,
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference41 articles.
1. de Vries E, Coebergh JW: Melanoma incidence has risen in Europe. BMJ. 2005, 331: 698-10.1136/bmj.331.7518.698.
2. Lipsker D, Engel F, Cribier B, Velten M, Hedelin G: Trends in melanoma epidemiology suggest three different types of melanoma. Br J Dermatol. 2007, 157: 338-343. 10.1111/j.1365-2133.2007.08029.x.
3. Welch HG, Woloshin S, Schwartz LM: Skin biopsy rates and incidence of melanoma: population based ecological study. BMJ. 2005, 331: 481-10.1136/bmj.38516.649537.E0.
4. de Vries E, Bray FI, Coebergh JW, Parkin DM: Changing epidemiology of malignant cutaneous melanoma in Europe 1969-1997 rising trends in incidence and mortality, but recent stabilisations in western Europe and decreases in Scandinavia. Int J Cancer. 2003, 107: 119-126. 10.1002/ijc.11360.
5. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P, eds: Cancer Incidence in Five Continents. 2007, International Agency for Research on Cancer (IARC) Scientific Publications, No. 160 Lyon, IARC, IX:
Cited by
42 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献