The role of loss of Y chromosome across the prostate cancer continuum

/ABSTRACT The goal of this K99/R00 Award is to accelerate Dr. Anqi Wang’s transition to an independent investigator in cancer and molecular epidemiology by supporting her research into the role of loss of the Y chromosome (LOY) across the prostate cancer continuum. This impactful project will investigate LOY both in leukocytes and prostate tumors to define its potential as a biomarker for etiology, detection, treatment, and prognosis. Dr. Wang is a postdoctoral fellow at Harvard T.H. Chan School of Public Health (HSPH). She holds a PhD in Genetic Epidemiology from the University of Southern California, where her work shed light on germline genetics of prostate cancer. Her plan will leverage her previous training and focus on new directions in 1) developing expertise in tissue-based and molecular biomarkers, 2) gaining clinical and pathological insights into prostate cancer, and 3) advancing leadership and collaborative networks. This plan involves targeted coursework, workshops, conferences, and mentorship from Drs. Lorelei Mucci, Philip Kantoff, Konrad Stopsack, Mitchell Machiela, and Massimo Loda. Her training will be mainly conducted at HSPH and Dana-Farber/Harvard Cancer Center, which provides robust networking, administrative, and educational support, supplemented with annual visits to Dr. Machiela’s lab at the National Cancer Institute and Dr. Loda’s lab at Weill Cornell Medicine for hands- on training in LOY detection. All mentors and advisors will guide her in faculty job applications and future grant writing to support Dr. Wang’s transition to independence. LOY is a common form of genetic mosaicism among men that is associated with increased all-cause mortality and chronic diseases, including prostate cancer. However, its clinical and etiologic impact on prostate cancer and translation has yet to be fully realized. The research will use large prospective cohorts to elucidate the multifaceted role of LOY across the prostate cancer continuum. During the K99 phase, Aim 1 focuses on LOY in leukocytes among cancer-free men, assessing its potential for early detection of prostate cancer and its etiologic role in molecular subtypes and germline genetic risk. The independent R00 phase investigates LOY in leukocytes and tumors in cancer patients. Aim 2 evaluates the impact of LOY in leukocytes on clinical outcomes, including survival and treatment response. Aim 3 examines the impact of LOY in prostate tumors on patient survival, and its joint effect with men's germline genetic risk and molecular subtypes. In summary, this project will provide novel insights into LOY as a biomarker for early detection, risk stratification, prognosis, and management of prostate cancer. This award will further Dr. Wang’s expertise in integrative molecular biomarker analysis and inform future R01 grant applications to improve prostate cancer risk assessments and treatment strategies, positioning her to become an independent researcher who elucidate the molecular mechanisms of prostate cancer and translate findings into actionable strategies. Project Number: 1K99CA303777-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Anqi Wang | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $129,058 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZCA1 RTRB-U (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11215751