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

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. GreggCherie 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number100070
JournalHuman Genetics and Genomics Advances
Volume3
Issue number1
DOIs
Publication statusPublished - 13 Jan 2022

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) grant P50CA180995 (W.J.C.) 08/01/15–07/31/20 NIH/NCI SPORE in Prostate Cancer PI on the SPORE grant, Center for Inherited Disease Research (CIDR) award from the NCI for patient sample genotyping ( X01HG009642 ), CIDR contract no. HHSN268201700006I , the Urological Research Foundation (W.J.C.), and the NorthShore University Health System , Evanston, IL, USA (B.T.H.). Additional support was provided by award numbers R01CA158627 and R01CA195505 (L.S.M.), P50 CA186786 (T.M.M.), UL1 TR000445 from NCATS/NIH for Vanderbilt REDCap (D.A.B.), P50 CA097186 and K05 CA175147 (J.L.S.), and U01 CA113913 (M.G.S.) from the NIH , and W81XWH-13-2-0074 (P.R.C.) from the Department of Defense .

Publisher Copyright:
© 2021 The Author(s)

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