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Keywords:

  • ARF;
  • CDKN2A;
  • FAM;
  • MPM;
  • point mutation;
  • splice site

Binni F, Antigoni I, De Simone P, Majore S, Silipo V, Crisi A, Amantea A, Pacchiarini D, Castori M, De Bernardo C, Catricalà C, Grammatico P. Novel and recurrent p14ARF mutations in Italian familial melanoma.

CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16INK4a and p14ARF, and originate from different open reading frames. Exon 1α is specific for p16INK4a, while exon 1β characterizes p14ARF. Most CDKN2A mutations are located in exons 1α and 2, while exon 1β variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16INK4a/CDK4 germline alterations and identified 15 p16INK4a and 1 CDK4 point mutations. In the present work, we extended our search to p14ARF mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14ARF mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.