These authors contributed equally to this work.
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
Article first published online: 4 JUN 2003
Copyright © 2003 John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 201, Issue 1, pages 109–118, September 2003
How to Cite
Ferreux, E., Lont, A. P., Horenblas, S., Gallee, M. P., Raaphorst, F. M., von Knebel Doeberitz, M., Meijer, C. J. and Snijders, P. J. (2003), 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., 201: 109–118. doi: 10.1002/path.1394
- Issue published online: 14 AUG 2003
- Article first published online: 4 JUN 2003
- Manuscript Accepted: 17 MAR 2003
- Manuscript Revised: 19 DEC 2002
- Manuscript Received: 1 OCT 2002
- penile carcinoma;
- human papillomavirus;
- p16INK4A pathway
A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16INK4A/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16INK4A 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 p16INK4A 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 p16INK4A/cyclin D/Rb pathway. Methylation of the p16INK4A 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 p16INK4A/cyclin D/Rb pathway can become disrupted during penile carcinogenesis. Copyright © 2003 John Wiley & Sons, Ltd.