New molecular tools for efficient screening of cervical cancer.

Cytological screening using the Pap-smear led to a remarkable reduction of the mortality of cervical cancer. However, due to subjective test criteria it is hampered by poor inter- and intra-observer agreement. More reproducible assays are expected to improve the current screening and avoid unnecessary medical intervention and psychological distress for the affected women. Cervical cancer arises as consequence of persistent high risk papillomavirus (HR-HPV) infections. Expression of two viral oncogenes, E6 and E7, in epithelial stem cells is required to initiate and maintain cervical carcinogenesis and results in significant overexpression of the cellular p16INK4a protein. Since this protein is not expressed in normal cervical squamous epithelia, screening for p16INK4a over-expressing cells allows to specifically identify dysplastic lesions, and significantly reduces the inter-observer disagreement of the conventional cytological or histological tests. Progression of preneoplastic lesions to invasive cancers is associated with extensive recombination of viral and cellular genomes which can be monitored by detection of papillomavirus oncogene transcripts (APOT assay) derived from integrated viral genome copies. Detection of integrated type oncogene transcripts points to far advanced dysplasia or invasive cancers and thus represents a progression marker for cervical lesions. These new assays discussed here will help to improve current limitations in cervical cancer screening, diagnosis, and therapy control.