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. Copyright © 2003 John Wiley & Sons, Ltd.