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.

Abstract

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.

• Authors: Emmanuelle Ferreux, Anne P Lont, Simon Horenblas, Maarten P W Gallee, Frank M Raaphorst, Magnus von Knebel Doeberitz, Chris J L M Meijer, Peter J F Snijders
• Journal: The Journal of pathology (J Pathol) Vol. 201 Issue 1 Pg. 109-18 (Sep 2003) ISSN: 0022-3417 [Print] England
• PMID: 12950023 (Publication Type: Journal Article)
• Copyright: Copyright 2003 John Wiley & Sons, Ltd.

Chemical References

• 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

Topics

• 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, 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)