Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

HGG advances. 2021 Nov 19 [Epub]

Yu Jiang, Travis J Meyers, Adaeze A Emeka, Lauren Folgosa Cooley, Phillip R Cooper, Nicola Lancki, Irene Helenowski, Linda Kachuri, Daniel W Lin, Janet L Stanford, Lisa F Newcomb, Suzanne Kolb, Antonio Finelli, Neil E Fleshner, Maria Komisarenko, James A Eastham, Behfar Ehdaie, Nicole Benfante, Christopher J Logothetis, Justin R Gregg, Cherie A Perez, Sergio Garza, Jeri Kim, Leonard S Marks, Merdie Delfin, Danielle Barsa, Danny Vesprini, Laurence H Klotz, Andrew Loblaw, Alexandre Mamedov, S Larry Goldenberg, Celestia S Higano, Maria Spillane, Eugenia Wu, H Ballentine Carter, Christian P Pavlovich, Mufaddal Mamawala, Tricia Landis, Peter R Carroll, June M Chan, Matthew R Cooperberg, Janet E Cowan, Todd M Morgan, Javed Siddiqui, Rabia Martin, Eric A Klein, Karen Brittain, Paige Gotwald, Daniel A Barocas, Jeremiah R Dallmer, Jennifer B Gordetsky, Pam Steele, Shilajit D Kundu, Jazmine Stockdale, Monique J Roobol, Lionne D F Venderbos, Martin G Sanda, Rebecca Arnold, Dattatraya Patil, Christopher P Evans, Marc A Dall'Era, Anjali Vij, Anthony J Costello, Ken Chow, Niall M Corcoran, Soroush Rais-Bahrami, Courtney Phares, Douglas S Scherr, Thomas Flynn, R Jeffrey Karnes, Michael Koch, Courtney Rose Dhondt, Joel B Nelson, Dawn McBride, Michael S Cookson, Kelly L Stratton, Stephen Farriester, Erin Hemken, Walter M Stadler, Tuula Pera, Deimante Banionyte, Fernando J Bianco, Isabel H Lopez, Stacy Loeb, Samir S Taneja, Nataliya Byrne, Christopher L Amling, Ann Martinez, Luc Boileau, Franklin D Gaylis, Jacqueline Petkewicz, Nicholas Kirwen, Brian T Helfand, Jianfeng Xu, Denise M Scholtens, William J Catalona, John S Witte

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA., Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Public Health Sciences, Seattle, WA 98109, USA., Fred Hutchinson Cancer Research Center, Cancer Epidemiology Program, Public Health Sciences, Seattle, WA 98109, USA., Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Departments of Genitourinary Medical Oncology and Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Department of Urology, David Geffen School of Medicine at UCLA, USA., Odette Cancer Centre, Sunnybrook Health and Sciences Centre, University of Toronto, Toronto, ON, Canada., Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Urology, University of California, San Francisco, San Francisco, CA, USA., Department of Urology, University of Michigan, Ann Arbor, MI, USA., Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, USA., Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA., Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands., Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Department of Urologic Surgery, University of California, Davis Medical Center, Sacramento, CA, USA., Department of Urology, Royal Melbourne Hospital and University of Melbourne, Australia., Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA., Department of Urology, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA., Mayo Clinic Department of Urology, Rochester, MN, USA., Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA., Department of Urology, University of Pittsburgh School of Medicine, PA, USA., Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., University of Chicago Comprehensive Cancer Center, Chicago, IL, USA., Urological Research Network, Miami Lakes, FL, USA., Departments of Urology and Population Health, New York University Langone Health and Manhattan Veterans Affairs Medical Center, New York, NY, USA., Department of Urology, Oregon Health and Science University, Portland, OR, USA., Genesis Healthcare Partners, Department of Urology, University of California, San Diego, CA, USA., Division of Urology, NorthShore University Health System, Evanston, IL, USA.

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