The authors investigated the prevalence and the distribution of mutations in these genes in different melanoma tissues. They screened 291 tumor tissues from 132 patients with melanoma. Paired samples of primary melanomas (102) and synchronous or asynchronous metastases from the same patients (165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (84), skin (36), visceral (25), brain (44) sites.
BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients.
p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples.
Conclusion. In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. The findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease. Starting from these findings, the prognostic value of such genetic alterations should be evaluated in a large cohort to assess whether the different distribution of BRAF/NRAS/p16CDKN2A mutations in tumor lesions may have an impact on disease outcome among patients with melanoma.
BRAF: BRAF is an isoform of RAF. Raf proteins (Raf-1, A-Raf, B-Raf) are intermediate to Ras and MAPK in the cellular proliferative pathway. Raf proteins are typically activated by Ras via phosphorylation, and activated Raf proteins in turn activate MAPK via phosphorylation. However, Raf proteins may also be
independently activated by other kinases.
NRAS: NRAS represents one of the three members of the Ras gene family (HRAS and KRAS are the remaining family members). The Ras proteins are typically small triphosphate-binding proteins, and are the common upstream molecule of several signaling pathways that play a key role in signal transduction, which results in cellular proliferation and transformation.
p16CDKN2A: Also known as p16, it binds to cyclin-dependent kinase 4 and 6, thereby preventing their interaction with cyclin D. It thus behaves as a negative regulator of proliferation and arrests cells in the G0/G1 phase of the cell cycle.
BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma
Journal of Clinical Oncology. Published online before print: May 21, 2012, doi: 10.1200/JCO.2011.41.2452.
Authors. M. Colombino, M. Capone, M. Maio, V. De Giorgi, A. Cossu, A. Lissia, C. Rubino, B. Massidda, S. Staibano, O. Nappi, G. Botti, C. Caraco, N. Mozzillo, A. Manca, M. Sini, P. A. Ascierto, G. Palmieri.
Affiliations. Italian Melanoma Intergroup (IMI); Istituto di Chimica Biomolecolare, CNR, Sassari, Italy; Istituto Nazionale Tumori Pascale, Naples, Italy; Universita Degli Studi Di Siena -Policlinico, Siena, Italy; Department of Dermatology, University of Florence, Florence, Italy; Istituto di Anatomia Patologica, AOU, Sassari, Italy; Chirurgia Plastica, Universita di Sassari, Sassari, Italy; Department of Medical Oncology, Hospital-University, Cagliari, Italy; Dipartimento Scienze Biomorfologiche e Funzionali, Universita Federico II di Napoli, Naples, Italy; AORN Cardarelli, Naples, Italy; Istituto Nazionale Tumori, Naples, Italy