Colombino, Maria and Sini, Maria Cristina and De Giorgi, Valeria and Lissia, Amelia and Massi, D. and Rubino, Corrado and Cossu, Antonio and Ayala, Fabrizio and Ascierto, Paolo Antonio and Palmieri, Giuseppe (2012) Multiple primary melanomas from same patients present discrepant somatic alterations in main candidate genes. Annals of oncology, Vol. 23 (Suppl. 9), p. 364. eISSN 1569-8041. Article.
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Background A series of patients with multiple primary melanoma (MPM) were screened for the involvement of the key-regulator genes in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease.
Methods Genomic DNA from peripheral blood of 63 MPM patients (54 cases with two primary melanomas, 8 with three, and 1 with four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified according to standardized criteria: 9 (14%) patients were classified as familial cases.
Paired synchronous and/or asynchronous MPM tissues (N = 100) from same patients (N = 46) were analyzed for somatic mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes.
Results Overall, 6 (10%) different CDKN2A germline mutations were identified: 5 inp1 6CDKN2A and 1 inp 14CDKN2A. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were significantly more frequent in patients with familial history of melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P < 0.001), and in patients with more than two melanomas (3/9; 33%) compared with patients with only two melanomas (3/54; 6%) (P = 0.012).
The debated A148T polymorphism was found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients (52% consistency).
Conclusions Coexistence of MPM and familial recurrence of melanoma as well as the presence of more than two melanomas seem to be strong indications to address patients to CDKN2A mutational screening. The low consistency in genetic patterns of primary tumors from the same patients provide additional evidence that pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly different cell types may be generated in multiple primary melanoma.
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