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by Amber K. Boehm, Ph.D.

Scientists are developing a better understanding of the relationship between human papillomavirus (HPV) and cervical cancer due to the efforts of researchers like Nicolas Wentzensen, M.D., Ph.D., a tenure-track investigator in the Hormonal and Reproductive Epidemiology Branch (HREB). In 2007, Dr. Wentzensen joined NCI as a visiting fellow from Heidelberg University in Germany, where he earned his M.D. and a Ph.D. in applied tumor biology. Dr. Wentzensen has always been interested in the etiology of cancers, and his clinical background helped guide his interest toward population-based research. He currently studies the origins of several gynecologic cancers and how to use that knowledge to improve screening and prevention efforts.

Dr. Wentzensen has been interested in cervical cancer for more than 15 years. Although it is known that infection with HPV causes cervical cancer, many HPV-infected women never develop cancer. In addition, women can be infected with multiple HPV strains of which only some may increase cancer risk. Research into what factors drive cancer formation, and the discovery of biomarkers that are harbingers of cancer progression, will allow more informed screening strategies to identify women most at risk of cervical cancer and to reduce unwarranted testing in women at low risk.

Dr. Wentzensen and his colleagues, including Mark Schiffman, M.D., M.P.H., a senior investigator in the Clinical Genetics Branch, recently found that although women may be infected with multiple HPV types, only one HPV strain, HPV 16, predominated in the discrete cervical biopsies in which precancerous cells were apparent. “This discovery confirms the dominant role of the HPV 16 strain in the causation of cervical cancer,” Dr. Wentzensen explained, “and contributes to data that indicate that screening women for specific HPV strains could identify those women most at risk of developing cancer.”

The American Cancer Society Screening Guidelines for the Prevention and Early Detection of Cervical Cancer, released this year, recommend HPV DNA and cytology (Pap smear) co-testing as a primary screening measure in women aged 30 to 65 years. Dr. Wentzensen was a member of one of the working groups for these guidelines. “These guidelines reflect the current evidence for HPV testing in cervical cancer,” Dr. Wentzensen said. “In addition to identifying women at risk of developing cervical cancer, it is clear that HPV-negative women do not require rigorous follow-up, allowing them to avoid unnecessary testing.” He believes that in the future, HPV detection and biomarker analysis could potentially take the place of all routine Pap smears. “Although we still need more evidence, it is likely that these HPV-based tests will allow more accurate prediction of a woman’s risk of developing cervical cancer than cytological tests,” he noted.

Dr. Wentzensen has investigated several viral and cellular characteristics that differ between normal and precancerous cervical cells in efforts to discover biomarkers of cancer progression. One characteristic under study is the methylation of HPV and host cell DNA, a phenomenon that Dr. Wentzensen examined in a large, population-based study at Kaiser Permanente in Northern California. In women infected with the most carcinogenic types of HPV, researchers found that methylation at specific sites in the HPV genome was more common in precancerous cells than in normal cells infected with HPV. Dr. Wentzensen has received several NCI competitive funding awards for his work on DNA methylation in gynecological cancers, including an NCI Director’s Intramural Innovation Award in 2012 to enable him to develop an HPV methylation assay.

Another potential biomarker for cervical cancer is the overexpression of p16, a cellular factor that Dr. Wentzensen translated to clinical application in his work at Heidelberg University. He now works with collaborators to assess the predictive potential of p16 in cytological samples from the Costa Rica HPV Vaccine Trial. Dr. Wentzensen also is collaborating with Kaiser Permanente to assess p16 as part of primary screening for cervical cancer. In addition, he complements his biomarker efforts by working with Sholom Wacholder, Ph.D., a senior investigator in the Biostatistics Branch, on principles of using biomarkers for risk stratification.

In contrast to cervical cancer, scientists have a more limited understanding of the origins of ovarian cancer, in part because ovarian cancer is highly heterogeneous, appearing in multiple forms. Louise A. Brinton, Ph.D., Chief of HREB, and Dr. Wentzensen are investigating a number of ovarian cancer risk factors, including oral contraceptive use and body mass index, which differ by cancer subtype. Dr. Wentzensen, together with Patricia Hartge, Sc.D., Deputy Director of the Epidemiology and Biostatistics Program, and extramural collaborators, is striving to create an ovarian cancer cohort consortium. “One goal of this work,” Dr. Wentzensen said, “is to improve the risk prediction models for ovarian cancer.” Similar to his work in cervical cancer, Dr. Wentzensen, with Mark E. Sherman, M.D., a senior clinician in HREB, is studying DNA methylation in ovarian cancer to determine whether differential methylation patterns correlate with distinct cancer subtypes.

Dr. Wentzensen joined NCI because it is home to leaders in HPV and cervical cancer. He enjoys the breadth of expertise among his colleagues. “It is difficult to name just a few key collaborators here at NCI, because the list is so long,” he said. “And it isn’t just principal investigators and staff scientists; students and fellows have made important contributions to this research. These projects are team efforts, and mentoring plays an integral role in this work.”