Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations

J Invest Dermatol. 2000 Jan;114(1):28-33. doi: 10.1046/j.1523-1747.2000.00823.x.


Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0-11. 1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1. 6-12.4), nevi on the feet (odds ratio 4.2; confidence interval 1. 4-12.5), total nevus number being at least 100 (nevi > or = 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0-11.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1. 1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1-3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genes, p16 / genetics*
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Likelihood Functions
  • Lod Score
  • Melanoma / genetics*
  • Melanoma / pathology
  • Nevus, Pigmented / genetics
  • Pedigree
  • Penetrance
  • Phenotype
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology