Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population

M G FitzGerald, D P Harkin, S Silva-Arrieta, D J MacDonald, L C Lucchina, H Unsal, E O'Neill, J Koh, D M Finkelstein, K J Isselbacher, A J Sober, D A Haber, Denis Harkin

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185 Citations (Scopus)


Five to ten percent of individuals with melanoma have another affected family member, suggesting familial predisposition. Germ-line mutations in the cyclin-dependent kinase (CDK) inhibitor p16 have been reported in a subset of melanoma pedigrees, but their prevalence is unknown in more common cases of familial melanoma that do not involve large families with multiple affected members. We screened for germ-line mutations in p16 and in two other candidate melanoma genes, p19ARF and CDK4, in 33 consecutive patients treated for melanoma; these patients had at least one affected first or second degree relative (28 independent families). Five independent, definitive p16 mutations were detected (18%, 95% confidence interval: 6%, 37%), including one nonsense, one disease-associated missense, and three small deletions. No mutations were detected in CDK4. Disease-associated mutations in p19ARF, whose transcript is derived in part from an alternative codon reading frame of p16, were only detected in patients who also had mutations inactivating p16. We conclude that germ-line p16 mutations are present in a significant fraction of individuals who have melanoma and a positive family history.

Original languageEnglish
Pages (from-to)8541-5
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
Publication statusPublished - 06 Aug 1996


  • Base Sequence
  • Carrier Proteins
  • Cell Cycle
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 9
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinases
  • DNA Primers
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Melanoma
  • Molecular Sequence Data
  • Point Mutation
  • Polymorphism, Genetic
  • Proteins
  • Proto-Oncogene Proteins
  • RNA Splicing
  • RNA, Messenger
  • RNA, Neoplasm
  • Retrospective Studies
  • Sequence Deletion
  • Tumor Suppressor Protein p14ARF


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