HPV-mediated transformation of the anogenital tract

Infection with high-risk human papillomavirus (HR-HPV) has been associated with intraepithelial neoplasia and carcinomas at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus. Although HR-HPV is a necessary cause for cervical cancer, the majority of anal cancers and a subset of cancers at other genital sites, additional (epi)genetic events are required for malignant transformation. HPV-mediated transformation of human epithelial cells has been recognized as a multi-step process resulting from deregulated transcription of the viral oncogenes E6 and E7 in the proliferating cells. Interference of E6 and E7 with cell cycle regulators induces genetic instability, which drives the continuous selection of oncogenic alterations providing cells with a malignant phenotype. Early genetic events during cervical carcinogenesis associated with immortalization, include deletions at chromosomes 3p, 6 and 10p, whereas amongst others gain of chromosome 3q, loss of chromosome 11 and epigenetic alterations such as inactivation of the TSLC1 tumor suppressor gene represent later events associated with tumor invasion.