HPV-induced carcinogenesis

Research Background

Infections with high-risk human papillomaviruses (HPVs) are causative events for cervical cancer, and subgroups of other anogenital cancers. In the course of various projects, we are studying the impact of this finding at the level of cancer prevention, diagnostics, risk stratification, test of cure, and prophylactic vaccination.

Our research has further incorporated an important translational pipeline involving the discovery of (epi)genetic, molecular mechanisms driving carcinogenesis, and clinical validation of disease biomarkers that result therefrom.
Towards these goals we are analysing specimens of patients with anogenital (pre)malignant disease (e.g. cervix, vulva, penis and anus) using to genome-wide screens and candidate gene approaches to identify relevant cellular alterations. Using in vitro studies on HPV-transformed human keratinocytes we have demonstrated that progression of an hrHPV-infected cell to an immortal and subsequent invasive phenotype results from the accumulation of specific (epi)genetic alterations in the host cell genome. Functional data from these model systems are used to complement studies on clinical samples to select the most promising biomarkers for risk stratification of premalignant disease. The candidate markers that result from these studies are subsequently evaluated on clinical sample series in order to select the best classifier and test algorithm. Finally, candidates are clinically validated, amongst others for their value in primary cervical screening using both cervical scrapings and self-collected (cervico-)vaginal samples.

Aim of the research program

• Improving effectiveness of cervical cancer screening (focus on gaining >sensitivity (via HPV testing or other biomarkers), >compliance (via self-sampling), and >specificity (molecular disease biomarkers used as triage test of HPV positive women or direct primary screening test)
• Improving risk stratification by molecular biomarkers of patients with premalignant ano-genital disease (CIN, VIN, AIN) for tailored treatment.
• Development of novel early detection biomarkers for ano-genital cancers detectable in cervico-vaginal, anal and urine samples

Methodology

Identification and functional characterization of oncogenic events as a basis for the discovery of new candidate biomarkers:

• Specimens representing sequence from premalignant to malignant disease (tissues, cervical scrapings, self-samples)
• Longitudinal in vitro model systems of primary keratinocytes in which hrHPV types are introduced (functional characterization)

Verification and clinical validation of biomarkers:

• Stored specimens in biobanks
• Prospective clinical and screening trials

Novel non-invasive cancer detection methods

For a number of non-HPV-induced cancers, such as endometrial cancer, ovarian cancer, bladder cancer, lung cancer and colorectal cancer, molecular tests primarily based on DNA methylation are being developed to enable their (early) detection in urine. This line of research is conducted in close collaboration with the Depts of Gynaecology, Urology, Pulmonology and Surgery.