Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment
Authors: Jiang Yu , Meyers Travis J. , Emeka Adaeze A. , Cooley Lauren Folgosa , Cooper Phillip R. , Lancki Nicola , Helenowski Irene , Kachuri Linda , Lin Daniel W. , Stanford Janet L. , Newcomb Lisa F. , Kolb Suzanne , Finelli Antonio , Fleshner Neil E. , Komisarenko Maria , Eastham James A. , Ehdaie Behfar , Benfante Nicole , Logothetis Christopher J. , Gregg Justin R. , Perez Cherie A. , Garza Sergio , Kim Jeri , Marks Leonard S. , Delfin Merdie , Barsa Danielle , Vesprini Danny , Klotz Laurence H. , Loblaw Andrew , Mamedov Alexandre , Larry Goldenberg S. , Higano Celestia S. , Spillane Maria , Wu Eugenia , Ballentine Carter H. , Pavlovich Christian P. , Mamawala Mufaddal , Landis Tricia , Carroll Peter R. , Chan June M. , Cooperberg Matthew R. , Cowan Janet E. , Morgan Todd M. , Siddiqui Javed , Martin Rabia , Klein Eric A. , Brittain Karen , Gotwald Paige , Barocas Daniel A. , Dallmer Jeremiah R. , Gordetsky Jennifer B. , Steele Pam , Kundu Shilajit D. , Stockdale Jazmine , Roobol Monique J. , Venderbos Lionne D.F. , Sanda Martin G. , Arnold Rebecca , Patil Dattatraya , Evans Christopher P. , Dall’Era Marc A. , Vij Anjali , Costello Anthony J. , Chow Ken , Corcoran Niall M. , Rais-Bahrami Soroush , Phares Courtney , Scherr Douglas S. , Flynn Thomas , Jeffrey Karnes R. , Koch Michael , Dhondt Courtney Rose , Nelson Joel B. , McBride Dawn , Cookson Michael S. , Stratton Kelly L. , Farriester Stephen , Hemken Erin , Stadler Walter M. , Pera Tuula , Banionyte Deimante , Bianco Fernando J. , Lopez Isabel H. , Loeb Stacy , Taneja Samir S. , Byrne Nataliya , Amling Christopher L. , Martinez Ann , Boileau Luc , Gaylis Franklin D. , Petkewicz Jacqueline , Kirwen Nicholas , Helfand Brian T. , Xu Jianfeng , Scholtens Denise M. , Catalona William J. , Witte John S. 
Published: August 2021

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 6,361 PC patients who 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 single nucleotide polymorphisms (SNPs) associated with conversion, 15 of which were not previously associated with PC risk. 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-SNP 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.