> Our Work > The Work We Fund

2023 John and Daria Barry Foundation- PCF VAlor Challenge Award

Germline Influence on Prostate Cancer Metastasis and Response to Androgen Deprivation Therapy

Principal Investigators: Tyler Seibert, MD, PhD (University of California San Diego), Rana McKay, MD (University of California San Diego), Paul Boutros, PhD, MBA (University of California Los Angeles)

Young Investigators: Roni Haas, PhD (University of California Los Angeles), Sophia Kamran, MD (Massachusetts General Hospital)

Co-Investigators: Felix Feng, MD (University of California San Francisco), Phuoc Tran, MD, PhD (University of Maryland), Alan Pollack, MD, PhD (University of Miami), Daniel Spratt, MD (University Hospitals / Case Western), Elai Davicioni, PhD (Veracyte), Isla Garraway, MD, PhD (University of California Los Angeles), Jason Vassy, MD, MPH (VA Boston Healthcare System)

Description:

  • Prostate cancer is the second most heritable solid malignancy, and inherited (germline) genetic factors play a major role in disease development and progression. While certain rare gene variants, such as BRCA2 alterations, increase the risk of metastatic prostate cancer, most patients inherit risk via the combination of many common genetic variants.
  • Polygenic risk scores (PRS) are genetic tools that can predict overall prostate cancer risk based on the combination of many common genetic variants. However, modifications are needed to use PRS tools to identify individuals at highest genetic risk for developing aggressive prostate cancer.
  • Tyler Seibert and colleagues have identified germline variants that can directly modulate tumor evolution and development of aggressive phenotypes, and are associated with clinical outcomes – these are called driver quantitative trait loci (dQTLs).
  • dQTLs also vary across ancestry groups and may explain some of the differences in tumor behavior across racial and ethnic groups. Thus, the use of dQTLs in clinical tools could improve patient management strategies and reduce racial/ethnic health disparities.
  • In this project, Dr. Seibert and team will determine whether a new “driver polygenic risk score” that uses dQTLs can predict the development of metastatic prostate cancer, as well as molecular and genomic prostate cancer features. This will be done using data and samples from VA patients and randomized phase 3 clinical trials with long-term follow-up data.
  • Whether dQTLs can predict tumor mutations and gene expression patterns or predict clinical outcomes after initial therapy with surgery or radiation, will also be investigated.
  • If successful, this project will result in a new clinical tool that can identify individuals at highest genetic risk for metastatic prostate cancer and help to guide treatment approaches in patients.
  • These studies will also help to improve understanding of the effects of inherited genetic features on prostate cancer clinical outcomes, elucidate biological contributions to health disparities, and prompt new lines of investigation to close ancestry-based gaps in our basic knowledge and clinical care.

What this means to patients: Prostate cancer is highly heritable, and tools that can identify individuals at highest genetic risk for aggressive disease will help to improve patient care and outcomes.  Dr. Seibert and team have identified genetic variants that increase prostate cancer aggressiveness and are using these to develop a new genetic test that can predict individuals at high risk for developing lethal prostate cancer and their responses to treatments. Ultimately, this new clinical tool will improve prostate cancer screening and treatment approaches and patient management, and help to reduce prostate cancer racial disparities.