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Discrepant alterations in main candidate genes among multiple primary melanomas

Maria Colombino1, MariaCristina Sini1, Amelia Lissia2, Vincenzo De Giorgi3, Ignazio Stanganelli4, Fabrizio Ayala5, Daniela Massi6, Corrado Rubino7, Antonella Manca1, Panagiotis Paliogiannis2, Susanna Rossari3, Serena Magi4, Laura Mazzoni4, Gerardo Botti5, Mariaelena Capone5, Marco Palla5, Paolo A Ascierto5, Antonio Cossu2, Giuseppe Palmieri1* and on behalf of the Italian Melanoma Intergroup (IMI)

Author Affiliations

1 Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR) - Traversa La Crucca 3, Baldinca Li Punti, 07100 Sassari, Italy

2 Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche, University of Sassari, Sassari, Italy

3 Department of Dermatology, University of Firenze, Firenze, Italy

4 Skin Cancer Unit, Istituto Scientifico Romagnolo per Studio e Cura dei Tumori, Meldola, Italy

5 Istituto Nazionale Tumori Fondazione Pascale, Napoli, Italy

6 Department of Pathology, University of Firenze, Firenze, Italy

7 Unit of Plastic Surgery, University of Salerno, Salerno, Italy

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Journal of Translational Medicine 2014, 12:117  doi:10.1186/1479-5876-12-117

Published: 8 May 2014



Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).


One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed for BRAF mutations and cKIT/CyclynD1 gene amplifications.


BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1 amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) and CyclinD1 (p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern of BRAF mutations as compared to incident primary tumors.


The low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.

Multiple melanoma; Mutation analysis; Gene amplification; Melanomagenesis; Molecular classification