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Megan Clarke Selected as Earl Stadtman Investigator in the Clinical Genetics Branch

, by DCEG Staff

In September 2020, Megan A. Clarke, Ph.D., M.H.S., was selected as an Earl Stadtman tenure-track investigator in the Clinical Epidemiology Unit (CEU) of the Clinical Genetics Branch (CGB). Dr. Clarke combines molecular, clinical, and population-based approaches to address etiology, prevention, and early detection of anogenital and endometrial cancers, yielding results that inform natural history and clinical management. She has designed and implemented several new studies that will establish long-term resources to address novel questions related to disease natural history and risk factors in racially diverse and underserved populations.

In her studies of cervical cancer, Dr. Clarke focuses on disparities (race, ethnicity, and other factors, such as obesity) and biomarker identification to improve screening and triage. With colleagues from the University of Mississippi Medical Center and The Mississippi State Department of Health, she initiated a statewide study of women undergoing cervical cancer screening in Mississippi. STRIDES (STudying Risks to Improve DisparitiES in cervical cancer in Mississippi) will enroll more than 30,000 women from a diverse population with over 50% African American women to explore novel questions related to disease natural history, cervical cancer risk assessment, and the performance of novel triage markers for cervical cancer screening, which may vary by race.

Her molecular research has helped to identify host gene and HPV DNA methylation as a promising biomarker in cervical carcinogenesis, one that outperforms current triage tests. She is collaborating with the Cancer Genome Research Laboratory, to develop a low-cost, next-generation sequencing methylation assay. Plans are underway to validate this assay in natural history studies and assess its potential for clinical use and in self-collected samples. In addition, Dr. Clarke is studying the association of methylation markers with anal precancers and cancers, an area in need of accurate biomarkers.

Recently, Dr. Clarke showed that obesity can lead to disparities in cancer screening. In a large cervical cancer screening population, she demonstrated that precancer detection was less successful in obese women, possibly accounting for 20% of cancers among screened women. She is following up this finding in epidemiologic analyses to determine at which stages these failures occur in the screening and management process.

Endometrial cancer is an understudied and underappreciated disease whose research lags behind that of other cancers in terms of natural history and clinical management. In response, Dr. Clarke is building a comprehensive endometrial cancer research portfolio, covering natural history, epidemiology and risk assessment, and biomarker development for early detection. Dr. Clarke led the first systematic review and meta-analysis quantifying the prevalence of postmenopausal bleeding in women with cancer (90%) and the risk of endometrial cancer among women with postmenopausal bleeding (9%). These findings suggest that targeting women with postmenopausal bleeding for early detection strategies will capture most endometrial cancers. Within Kaiser Permanente Northwest (KPNW) she will assess somatic mutations, methylation, and proteomics in endometrial precursor lesions with and without a subsequent cancer diagnosis to discover biomarkers and risk factors associated with progression of endometrial hyperplasia to cancer. She will validate these findings in a prospective cohort study conducted at the Mayo Clinic, designed to evaluate risk prediction strategies and novel early detection approaches in women with abnormal uterine bleeding. The study includes self-collection of an intravaginal tampon, as well as collection of material from the uterine lining using a Tao brush. This study establishes a rich resource that will integrate clinical, epidemiologic, and biomarker data in a population of women at elevated risk for endometrial cancer.

In analyses of hysterectomy-corrected endometrial cancer incidence rates and survival in the Surveillance and Epidemiology and End Results (SEER) database, Dr. Clarke showed that recent increases in endometrial cancer incidence have been primarily due to rising rates of aggressive, non-endometrioid subtypes which are less strongly associated with well-established risk factors like obesity. Among non-Hispanic black women, rates of non-endometrioid subtypes were twice as high compared to other groups, and five-year relative survival was lower across all stages and subtypes, highlighting strong racial disparities. To better understand the etiology and natural history of these aggressive subtypes and differences by race, Dr. Clarke designed the DETECT Study (Discovery and Evaluation of Tests for Endometrial Cancer in Tampons), to assess endometrial cancer risk factors and evaluate the performance of biomarkers measured in tissue and vaginal tampons in women undergoing hysterectomy for endometrial cancer or benign conditions at the University of Alabama.

Her research has contributed to the scientific evidence that support the newly published clinical management guidelines for cervical cancer; Dr. Clarke also served on the guidelines committee for cervical cancer and is a working group leader on the International Anal Neoplasia’s Society’s Task Force to develop anal cancer screening guidelines.  

Dr. Clarke earned an M.H.S. in biochemistry and molecular biology in 2010 and a Ph.D. in epidemiology in 2016, both from the Johns Hopkins Bloomberg School of Public Health. Prior to completing her Ph.D., she was a postbaccalaureate fellow in CGB working with Mark Schiffman, M.D., M.P.H., on human papillomavirus (HPV) molecular epidemiology and natural history studies. Dr. Clarke returned to DCEG in 2016 as an NCI Cancer Prevention Fellow and was promoted to research fellow in 2019. During her fellowship under the mentorship of Nicolas Wentzensen M.D., Ph.D., M.S., she focused on molecular epidemiologic studies of gynecological cancers, with a particular focus on etiologic biomarkers that have a high potential for improving early detection and risk stratification. She has received several internal and external awards for her work. In 2018 she was selected for the William G. Coleman, Jr., Ph.D., Minority Health and Health Disparities Research Innovation Award.

 

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