BRAF gene contributes to melanoma pathogenesis but not to melanoma susceptibility

9584 Background: Somatic mutations of the BRAF gene has been recently reported in about two thirds of patients with malignant melanoma (MM). We here defined the contribution of BRAF to melanoma susceptibility, also making a comparison with the prevalence of CDKN2A germline mutations in MM patients from different geographical areas in Italy. Methods: Using a combination of DHPLC analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 melanoma patients (211 from North Italy and 358 from South Italy) were screened for BRAF mutations. Results: Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in 4/569 (0.7%) melanoma patients. High frequency (59%) of BRAF mutations was instead observed in tumor samples from cases also undergoing germline DNA analysis; at somatic level, substitution of valine 599 was found to account for majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively-collected patients originating from South Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected. Conclusions: Our study provides a clear assessment that mutational activation of the BRAF gene is a pathogenetic event contributing to melanoma tumorigenesis at somatic level with nearly absent participation to MM predisposition at germline level. Although at lower frequency in our population, germline CDKN2A mutations have been instead demonstrated to remain the major gene involved into the melanoma susceptibility. Work was supported by Associazione Italiana Ricerca sul Cancro and Regione Autonoma Sardegna. No significant financial relationships to disclose.