Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus

J Pathol. 2003 Sep;201(1):109-18. doi: 10.1002/path.1394.


A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16(INK4A)/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16(INK4A) expression and promoter methylation, and expression of the BMI-1 polycomb gene product were studied. Sixteen (30%) of the carcinomas were found to harbour high-risk HPV DNA, 15 of which contained HPV 16. HPV 16 E6/E7 oncogene transcripts were detected in 13 (87%) of the carcinomas that contained HPV 16. Strong immunostaining for p16(INK4A) was significantly more frequent in carcinomas that contained high-risk HPV DNA (p < 0.001) and amongst those with HPV 16 DNA, it was more frequent in lesions in which E6/E7 transcripts were detectable (p = 0.029). This supports an active role for HPV E7 in interfering with the p16(INK4A)/cyclin D/Rb pathway. Methylation of the p16(INK4A) promoter or overexpression of the BMI-1 polycomb gene product may provide alternative modes of interference with this pathway. These phenomena were mutually exclusive and found in the absence of HPV in 15% and 10% of the penile carcinomas, respectively. These data indicate that there are at least three plausible mechanisms by which the p16(INK4A)/cyclin D/Rb pathway can become disrupted during penile carcinogenesis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Transformation, Neoplastic / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • DNA Methylation
  • DNA, Viral / analysis
  • Genes, p16
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Papillomaviridae / isolation & purification*
  • Papillomavirus Infections / complications*
  • Penile Neoplasms / metabolism*
  • Penile Neoplasms / virology
  • Polycomb Repressive Complex 1
  • Polymerase Chain Reaction / methods
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / metabolism
  • RNA, Viral / analysis
  • Repressor Proteins*
  • Tumor Virus Infections / complications*


  • BMI1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Viral
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Viral
  • Repressor Proteins
  • Polycomb Repressive Complex 1