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Assessment of germline and somatic alterations in main candidate genes among patients with multiple primary melanoma


A series of patients with multiple primary melanoma (MPM) has been studied for assessing frequency and distribution of alterations in candidate genes involved in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease.


Two hundred and twenty-seven genomic DNA samples from paired synchronous and/or asynchronous tumour tissues of 106 MPM patients (92 cases with two, 13 with three, and 1 with four primary melanomas) were screened for somatic mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes. For 87 (84%) MPM patients from our series, peripheral blood was available and germline DNAs was analyzed for mutations in p16CDKN2A and p14CDKN2A genes. All mutation analyses we performed by direct automated DNA sequencing. Family history for melanoma was defined according to standardized criteria.


At somatic level, BRAF mutations were identified in 108/227 (48%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 8/208 (4%) and 28/204 (14%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients [55/106 (52%) discrepant cases). Among them, 35/106 (33%) patients presented discrepant MPM lesions according to the BRAF mutation status. Among the 87 MPM patients whose germline DNA was available, 8 (9%) of them showed different CDKN2A germline mutations: 7 in p16CDKN2A and 1 in p14CDKN2A. Assessment of family history for melanoma revealed that 13/87 (15%) patients presented at least one additional family member affected; a total of ≥ 3 melanomas in family was observed in 20/87 (23%) cases of our series. The CDKN2A germline mutations were found significantly more frequent in patients with familial history of melanoma (7/13; 54%) compared with patients without (1/74; 1.4%) (P<0.001); analogously, CDKN2A mutations were observed in 1/67 (1.5%) and 7/20 (35%) patients with 2 and 3 or more melanomas in family, respectively (P<0.001).


The low consistency in mutation patterns at somatic level among MPM lesions from the same patients provide further evidence that melanomagenesis is heterogeneous and molecularly different cell types may participate to the development of multiple melanomas. Our findings on germline DNA indicate that occurrence of at least 3 melanomas (in patients or families) or familial recurrence of melanoma may represent strong indicators to address patients to CDKN2A mutation screening.

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Correspondence to Maria Colombino.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Colombino, M., Sini, M.C., Lissia, A. et al. Assessment of germline and somatic alterations in main candidate genes among patients with multiple primary melanoma. J Transl Med 12 (Suppl 1), O3 (2014).

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