Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations

J Natl Cancer Inst. 2000 Jun 21;92(12):1006-10. doi: 10.1093/jnci/92.12.1006.


Background: Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer.

Methods: We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families. We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi. The three recurrent mutations were haplotyped. All P values were two-sided.

Results: The median age at CMM diagnosis (P =.70) and the median numbers of CMMs (P =.73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P =.80) or in tumor number (P =.24). There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P =.004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi. Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3). Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes.

Conclusions: The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families.

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Arginine / genetics
  • Aspartic Acid / genetics
  • Cyclin-Dependent Kinases / genetics*
  • Cysteine / genetics
  • Genes, p16 / genetics*
  • Genotype
  • Germ-Line Mutation*
  • Glycine / genetics
  • Haplotypes
  • Humans
  • Melanoma / epidemiology
  • Melanoma / genetics*
  • Middle Aged
  • Nevus / genetics
  • Pancreatic Neoplasms / epidemiology
  • Pancreatic Neoplasms / genetics*
  • Phenotype
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / genetics*
  • Statistics, Nonparametric
  • Tryptophan / genetics
  • United States / epidemiology
  • Valine / genetics


  • Aspartic Acid
  • Tryptophan
  • Arginine
  • Cyclin-Dependent Kinases
  • Valine
  • Cysteine
  • Glycine