Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition

Melanoma Res. 2011 Jun;21(3):175-9. doi: 10.1097/CMR.0b013e328343eca2.


The reported frequencies of germline mutations in the melanoma candidate genes are low in patients with uveal melanoma (UM). However, the number of families studied is limited and the majority of the published reports used low-sensitivity techniques for mutational screening. Identifying the frequency of alterations in any of the melanoma genes in patients with UM with increased hereditary cancer risk is important for proper counseling of these patients. We studied a total of 47 patients with UM including three with a family history of UM, 18 with a family and/or personal history of cutaneous melanoma (CM), three with early age at diagnosis (<30), 11 with increased risk for a known familial cancer syndrome, and 12 with a second primary tumor. Germline screening for mutations in CDKN2A, p14ARF, and exon 2 of CDK4 was carried out by direct sequencing. We identified a variant (IVS1-69 C>T) of uncertain significance in exon 1b of p14ARF in one of the patients with UM and his mother who also had UM. The variant was neither detected in any of the other patients with UM nor in 146 controls. We did not identify pathogenic mutations in CDKN2A nor exon 2 of CDK4 gene. Our study supports the low frequency of germline mutation of the CM candidate genes in patients with UM with family histories suggestive of a high risk for hereditary cancer. Germline testing for CDKN2A might be reserved for patients with UM with a family history of two or more CM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • Genes, p16*
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Male
  • Melanoma / genetics*
  • Middle Aged
  • Polymorphism, Restriction Fragment Length
  • Tumor Suppressor Protein p14ARF / genetics*
  • Uveal Neoplasms / genetics*


  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4

Supplementary concepts

  • Uveal melanoma