The CDKN2A/p16INK4a 5'UTR sequence and translational regulation: Impact of novel variants predisposing to melanoma

Virginia Andreotti, Alessandra Bisio, Brigitte Bressac-de Paillerets, Mark Harland, Odile Cabaret, Julia Newton-Bishop, Lorenza Pastorino, William Bruno, Roberto Bertorelli, Veronica De Sanctis, Alessandro Provenzani, Chiara Menin, Gilberto Fronza, Paola Queirolo, Robert C. Spitale, Giovanna Bianchi-Scarrà, Alberto Inga, Paola Ghiorzo

Research output: Contribution to journalArticlepeer-review


Many variants of uncertain functional significance in cancer susceptibility genes lie in regulatory regions, and clarifying their association with disease risk poses significant challenges. We studied 17 germline variants (nine of which were novel) in the CDKN2A 5'UTR with independent approaches, which included mono and bicistronic reporter assays, Western blot of endogenous protein, and allelic representation after polysomal profiling to investigate their impact on CDKN2A mRNA translation regulation. Two of the novel variants (c.-27del23, c.-93-91delAGG) were classified as causal mutations (score ≥3), along with the c.-21C>T, c.-34G>T, and c.-56G>T, which had already been studied by a subset of assays. The novel c.-42T>A as well as the previously described c.-67G>C were classified as potential mutations (score 1 or 2). The remaining variants (c.-14C>T, c.-20A>G, c.-25C>T+c.-180G>A, c.-30G>A, c.-40C>T, c.-45G>A, c.-59C>G, c.-87T>A, c.-252A>T) were classified as neutral (score 0). In conclusion, we found evidence that nearly half of the variants found in this region had a negative impact on CDKN2A mRNA translation, supporting the hypothesis that 5'UTR can act as a cellular Internal Ribosome Entry Site (IRES) to modulate p16INK4a translation.

Original languageEnglish
Pages (from-to)210-221
Number of pages12
JournalPigment Cell and Melanoma Research
Issue number2
Publication statusPublished - Mar 1 2016


  • 5' untranslated region
  • CDKN2A
  • Germline mutation
  • Melanoma susceptibility
  • Polysomal imbalance
  • Reporter assays
  • Variants with unknown functional significance

ASJC Scopus subject areas

  • Dermatology
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)


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