Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A

J Am Acad Dermatol. 2011 Aug;65(2):281-288. doi: 10.1016/j.jaad.2010.06.044. Epub 2011 May 12.


Background: About 10% of cutaneous malignant melanomas (CMM) occur in individuals with a family history of melanoma. In 20% to 40% of melanoma families germline mutations in CDKN2A are detected. Knowledge of the clinicohistologic characteristics of melanomas and patients from these families is important for optimization of management strategies, and may shed more light on the complex interplay of genetic and environmental factors in the pathogenesis of melanoma.

Objective: We sought to investigate the clinical and histologic characteristics of CMM in CDKN2A-mutated families.

Methods: Clinical and histologic characteristics of 182 patients with 429 CMM from families with a founder mutation in CDKN2A (p16-Leiden mutation) were compared with 7512 patients with 7842 CMM from a population-based cancer registry.

Results: Patients with p16-Leiden had their first melanoma 15.3 years younger than control patients. The 5-year cumulative incidence of second primary CMM was 23.4% for patients with p16-Leiden compared with 2.3% for control patients. The risk of a second melanoma was twice as high for patients with p16-Leiden who had their first melanoma before age 40 years, compared with older patients with p16-Leiden. Unlike control patients, there was no body site concordance of the first and second melanoma in patients with p16-Leiden and multiple primary melanomas. Patients with p16-Leiden had significantly more superficial spreading, and less nodular and lentiginous melanomas.

Limitations: Ascertainment of patients with p16-Leiden was family based. The study was performed in families with a founder mutation, the p16-Leiden mutation.

Conclusion: Our findings are consistent with a pathogenic pathway of melanoma development from nevi, starting early and ongoing throughout life, and not related to chronic sun exposure.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Distribution
  • Age of Onset
  • Aged
  • Biopsy, Needle
  • Case-Control Studies
  • Databases, Factual
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, p16*
  • Genetic Predisposition to Disease / epidemiology*
  • Germ-Line Mutation
  • Humans
  • Immunohistochemistry
  • Incidence
  • Male
  • Melanoma / epidemiology
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Middle Aged
  • Neoplasm Staging
  • Pedigree
  • Prognosis
  • Reference Values
  • Registries
  • Risk Assessment
  • Sex Distribution
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology*
  • Survival Analysis