Molecular events leading to HPV-induced high grade neoplasia

Abstract

Cervical cancer is initiated by high-risk types of the human papillomavirus (hrHPV) and develops via precursor stages, called cervical intraepithelial neoplasia (CIN). High-grade CIN lesions are considered true precancerous lesions when the viral oncogenes E6 and E7 are aberrantly expressed in the dividing cells. This results in abolishment of normal cell cycle control via p53 and pRb degradation. However, it has become clear that these viral oncogenes possess additional oncogenic properties, including interference with the DNA methylation machinery and mitotic checkpoints. Identification of the resulting molecular events leading to high-grade neoplasia will 1) increase our understanding of cervical carcinogenesis, 2) yield biomarkers for early diagnosis, and 3) identify therapeutic targets for HPV-induced (pre) cancerous lesions. This review will briefly summarise current advances in our understanding of the molecular alterations in the host cell genome that occur during HPV-induced carcinogenesis.

Fig. 1

Schematic representation of HPV-mediated cervical carcinogenesis. Progression of a high-grade CIN lesion, characterized by viral oncogene expression in dividing cells (i.e. a transforming infection), to invasive cancer results from the accumulation of DNA changes induced by HPV. High-grade CIN represents a heterogeneous stage of disease with varying duration of existence (up to 30 years). ‘Advanced’ lesions show a cancer-like profile including hypermethylation of tumour suppressor genes and specific chromosomal alterations. Complementary somatic mutations only become detectable at the stage of invasive cancer. CIN: cervical intraepithelial neoplasia; TSG: tumour suppressor gene.