Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma
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RESEARCH
Open Access
Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma Maria Colombino1, Amelia Lissia2, Mariaelena Capone3, Vincenzo De Giorgi4, Daniela Massi5, Ignazio Stanganelli6, Ester Fonsatti7, Michele Maio7, Gerardo Botti3, Corrado Caracò3, Nicola Mozzillo3, Paolo A Ascierto3, Antonio Cossu2† and Giuseppe Palmieri1*†
Abstract Background: Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Methods: Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. Results: Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and nonSardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. Conclusions: Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease. Keywords: Malignant melanoma, BRAF gene, NRAS gene, Mutation analysis, Cancer genetic heterogeneity
Introduction Melanoma is characterized by a high tendency to metastasize and a striking resistance to conventional therapies other than surgery [1,2]. Recently, kinase-targeted therapies and immunostimulatory antibodies or a combination of them have been successfully introduced into the treatment of melanoma [3-7]. From the pathogenetic point of view, melanoma is a complex disease that arises thorough activation of several crucial cell-signaling pathways * Correspondence: [email protected] † Equal contributors 1 Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Traversa La Crucca 3, Baldinca Li Punti 07100, Sassari, Italy Full list of author information is available at the end of the article
[8,9]. A better comprehension of the molecular mechanisms underlying the development and progression of melanoma is valuable in assessing the different biological subset of patients to be addressed to the most appropriate therapy. Among others, the mitogen-
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