Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma

Nat Genet. 1999 Jan;21(1):128-32. doi: 10.1038/5082.


Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions*
  • Alleles
  • Cell Line, Transformed
  • Codon, Initiator*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Guanine*
  • Humans
  • Male
  • Melanoma / genetics*
  • Mutation*
  • Pedigree
  • Protein Biosynthesis
  • Thymine*
  • Transcription, Genetic


  • 5' Untranslated Regions
  • Codon, Initiator
  • Cyclin-Dependent Kinase Inhibitor p16
  • Guanine
  • Thymine