1118PD - Multiple primary melanomas from same patients present discrepant somatic alterations in main candidate genes

Date 29 September 2012
Event ESMO Congress 2012
Session Basic Science and Translational Research I
Topics Melanoma and other Skin Tumours
Pathology/Molecular Biology
Presenter Maria Colombino
Authors M. Colombino1, M. Sini2, V. De Giorgi3, A. Lissia4, D. Massi5, C. Rubino6, A. Cossu4, F. Ayala7, P.A. Ascierto7, G. Palmieri2
  • 1Unit Of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, 07100 - Sassari/IT
  • 2Unit Of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, Sassari/IT
  • 3Department Of Dermatology, University of Florence, Florence/IT
  • 4Institute Of Pathology, University of Sassari, Sassari/IT
  • 5Institute Of Pathology, University of Florence, Florence/IT
  • 6Plastic Surgery, University of Sassari, Sassari/IT
  • 7Melanoma, National Tumor Institute Fondazione Pascale, Naples/IT

Abstract

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 inp16CDKN2A and 1 inp14CDKN2A. 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.

Disclosure

All authors have declared no conflicts of interest.