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. 2018 Jan 3;9(9):8531-8541.
doi: 10.18632/oncotarget.23989. eCollection 2018 Feb 2.

Genetic alterations in main candidate genes during melanoma progression

Maria Cristina Sini  1 , Valentina Doneddu  2 , Panagiotis Paliogiannis  3 , Milena Casula  1 , Maria Colombino  1 , Antonella Manca  1 , Gerardo Botti  4 , Paolo A Ascierto  4 , Amelia Lissia  2 , Antonio Cossu  2 , Giuseppe Palmieri  1
Affiliations

Genetic alterations in main candidate genes during melanoma progression

Maria Cristina Sini et al. Oncotarget. .

Abstract

Cutaneous melanoma is a common and aggressive human skin cancers. Much is actually known about the molecular mechanisms underlying melanoma pathogenesis. The aim of the study was to evaluate any possible correlation between mutations in main growth-controlling genes (BRAF, NRAS, CDKN2A) and copy number variations in frequently amplified candidate genes (MITF, EGFR, CCND1, cMET, and cKIT) during melanoma initiation and progression. A large series of primary and secondary melanoma tissue samples (N = 274) from 232 consecutively-collected patients of Italian origin as well as 32 tumor cell lines derived from primary and metastatic melanomas underwent mutation screening and fluorescence in situ hybridization (FISH) analysis. Overall, BRAF, NRAS, and CDKN2A were found mutated in 62.5%, 12.5% and 59% cell lines and in 47%, 16%, 12% tumor tissues, respectively. Quite identical mutation patterns between primary tumors and metastatic lesions were found for BRAF and NRAS genes; mutations of CDKN2A gene appeared to be instead selected during tumor progression. In cell lines, high rates of gene amplifications were observed (varying from 12.5% for cKIT to 50% for MITF); vast majority of cell lines (75%) presented at least one amplified gene. Conversely, prevalence of gene amplification was significantly and progressively decreasing in melanoma metastases (12%) and primary melanomas (4%). Our findings suggest that gene amplifications may be acquired during the late phases of melanoma evolution and mostly act as "passenger" or "non-causative" alterations.

Keywords: fluorescence in situ hybridization (FISH) analysis; genetic heterogeneity; malignant melanoma; mutation analysis; oncogenic driver genes.

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Conflict of interest statement

CONFLICTS OF INTEREST Paolo A. Ascierto has/had consultant and advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche-Genenetech, Novartis, Ventana Medical Systems, Inc, and Amgen. He received research fund from Bristol Myers Squibb, Roche-Genetech, and Ventana. All the remaining authors declare the absence of any conflicts of interest.

Figures

Figure 1
Figure 1. Distribution of gene amplifications in melanoma samples
(A) Tumor tissues presenting multiple gene amplifications. (B) Paired melanoma samples from the same patients. Individual gene amplifications (gray squares) are shown across all cases. The patients with consistent patterns of gene amplification between primary and metastatic melanoma tissues are indicated by the suffix “c”.
See this image and copyright information in PMC

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