Genetic factors associated with prostate cancer conversion from active surveillance to treatment

• Published in: HGG advances Vol. 3; no. 1; p. 100070
• Main 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, Goldenberg, S. Larry, Higano, Celestia S., Spillane, Maria, Wu, Eugenia, Carter, H. Ballentine, 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, Karnes, R. Jeffrey, 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.01.2022; Elsevier
• Subjects: genetics; genome-wide association study; prostate; prostatic neoplasms; prostate; genetics; prostatic neoplasms; genome-wide association study
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2021.100070

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 PC, 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. Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.