Casula, Milena and Colombino, Maria and Satta, Maria Paola and Cossu, Antonio and Ascierto, Paolo Antonio and Bianchi Scarrà, Giovanna and Castiglia, Daniele and Budroni, Mario and Rozzo, Carla and Manca, Antonella and Lissia, Amelia and Carboni, Annangela and Petretto, Elisabetta and Satriano, Sabrina Maria Rosaria and Botti, Gerardo and Mantelli, Michela and Ghiorzo, Paola and Stratton, Michael R. and Tanda, Francesco and Palmieri, Giuseppe (2004) BRAFgene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: the Italian melanoma intergroup study. Journal of clinical oncology, Vol. 22 (2), p. 286-292. ISSN 0732-183X. eISSN 1527-7755. Article.
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Oncogenic activation of the BRAF gene has been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). In this study, we investigated the contribution of BRAF to melanoma susceptibility, also making a comparison with frequency of CDKN2A germline mutations in MM patients from different areas in Italy.
Patients and Methods
Using a combination of denaturing high-performance liquid chromatography analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 MM patients (211 from northern Italy and 358 from southern Italy) were screened for BRAF mutations.
Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in four (0.7%) of 569 MM patients. The most common BRAF mutation, V599E, was detected in one germline DNA sample only; M116R and G608H were newly described mutations. A high frequency (59%) of BRAF mutations was instead observed in tumor samples from patients also undergoing germline DNA analysis; at the somatic level, substitution of valine 599 was found to account for the majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively collected patient samples originating in southern Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected.
Mutation analysis of either blood DNA from a large collection of MM patients or matched MM tissues from a subset of such patients revealed that BRAF is somatically mutated and does not play a major role in melanoma susceptibility. The present study further suggests that patient origin may account for different mutation rates in candidate genes.
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