Inactivation of the CDKN2A and the p53 tumour suppressor genes in external genital carcinomas and their precursors

Br J Dermatol. 2007 Mar;156(3):448-53. doi: 10.1111/j.1365-2133.2006.07604.x.


Background: p53 has been extensively studied in external genital carcinoma (EGC), and is frequently inactivated, but little is known about the role of the CDKN2A tumour suppressor gene in the oncogenesis of EGC.

Objectives: To investigate the role of CDKN2A and p53 in the pathogenesis of EGCs and their precursor lesions vulval intraepithelial neoplasia (VIN3), penile intraepithelial neoplasia and lichen sclerosus (LS).

Methods: By means of CDKN2A and p53 mutation screening (single-strand conformational polymorphism analysis and sequencing), methylation analysis of alternative CDKN2A promoters (methylation-specific polymerase chain reaction) and p53 immununochemistry, we analysed eight invasive EGCs (five from vulva and three from penis) and 25 precancerous lesions (two undifferentiated VIN3 and 23 vulval/penile lesions of LS) from 33 patients.

Results: p53 mutations (mainly transversions) and CDKN2A mutations (including one hot spot) were present in 75% and 50% of invasive tumours, respectively, but were absent in all precancerous lesions. Remarkably, all CDKN2A-mutated tumours also harboured a p53 mutation. CDKN2A or p53 mutations were observed more frequently in LS-derived EGCs than in human papillomavirus-derived EGCs (P = 0.053). A positive anti-p53 staining, but without p53 mutations, was also detected in 30% of LS lesions, suggesting a p53 stabilization in response to inflammation and carcinogenic insult. Methylation of p16(INK4a) and p14(ARF) promoters was not a frequent mechanism of CDKN2A inactivation.

Conclusions: Our study shows a high prevalence of co-inactivating mutations of p53 and/or CDKN2A genes in EGC, that seem to occur preferentially in LS-derived tumours and late in oncogenesis.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Carcinoma in Situ / genetics
  • Cell Transformation, Neoplastic / genetics
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • Female
  • Gene Silencing*
  • Genes, p16*
  • Genes, p53*
  • Humans
  • Lichen Sclerosus et Atrophicus / genetics
  • Male
  • Middle Aged
  • Penile Neoplasms / genetics*
  • Polymorphism, Single-Stranded Conformational
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism
  • Promoter Regions, Genetic / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Vulvar Lichen Sclerosus / genetics
  • Vulvar Lichen Sclerosus / metabolism
  • Vulvar Neoplasms / genetics*
  • Vulvar Neoplasms / metabolism


  • DNA, Neoplasm
  • Tumor Suppressor Protein p53