1. Genetic factors associated with prostate cancer conversion from active surveillance to treatment
- Author
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Marc A. Dall'Era, R. Jeffrey Karnes, Jacqueline Petkewicz, Michael S. Cookson, Eric A. Klein, Soroush Rais-Bahrami, Jeremiah R. Dallmer, Kelly L. Stratton, Phillip R. Cooper, Denise M. Scholtens, James A. Eastham, Janet L. Stanford, Rebecca S. Arnold, Peter R. Carroll, S. Larry Goldenberg, Monique J. Roobol, Niall M. Corcoran, Lisa F. Newcomb, Stephen Farriester, Antonio Finelli, Nicola Lancki, Nataliya Byrne, Thomas Flynn, Neil E. Fleshner, Anthony J. Costello, Christian P. Pavlovich, Rabia Martin, Matthew R. Cooperberg, John S. Witte, Ann Martinez, Leonard S. Marks, Lauren Folgosa Cooley, Mufaddal Mamawala, Martin G. Sanda, Lionne D.F. Venderbos, Joel B. Nelson, Maria Spillane, Nicholas Kirwen, Sergio Garza, Erin Hemken, William J. Catalona, Shilajit Kundu, Paige Gotwald, Courtney Phares, Fernando J. Bianco, Tuula Pera, Justin R. Gregg, Todd M. Morgan, June M. Chan, Dawn McBride, Courtney Rose Dhondt, Andrew Loblaw, Jeri Kim, Maria Komisarenko, Brian T. Helfand, Deimante Banionyte, Karen Brittain, Janet E. Cowan, Christopher P. Evans, Walter M. Stadler, Danny Vesprini, Linda Kachuri, Franklin Gaylis, Danielle Barsa, Yu Jiang, Javed Siddiqui, Cherie Perez, Isabel H. Lopez, Daniel W. Lin, Travis J. Meyers, Alexandre Mamedov, Tricia Landis, Ken Chow, Luc Boileau, Douglas S. Scherr, Christopher J. Logothetis, Celestia S. Higano, Merdie Delfin, Stacy Loeb, Adaeze A. Emeka, Anjali Vij, Jennifer B. Gordetsky, Irene Helenowski, Laurence Klotz, Pam Steele, Suzanne Kolb, Eugenia Wu, Christopher L. Amling, DA Barocas, Samir S. Taneja, Michael O. Koch, Dattatraya Patil, Behfar Ehdaie, Jazmine Stockdale, Nicole Benfante, H. Ballentine Carter, Jianfeng Xu, and Urology
- Subjects
Urologic Diseases ,Oncology ,Aging ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Single-nucleotide polymorphism ,Genome-wide association study ,QH426-470 ,Article ,prostatic neoplasms ,Prostate cancer ,SDG 3 - Good Health and Well-being ,Clinical Research ,Prostate ,Internal medicine ,Genetics ,medicine ,genetics ,Genetic risk ,Genetics (clinical) ,Cancer ,prostate ,genome-wide association study ,business.industry ,Prevention ,Prostate Cancer ,Human Genome ,Hazard ratio ,medicine.disease ,Confidence interval ,Management strategy ,medicine.anatomical_structure ,Molecular Medicine ,Active treatment ,business - Abstract
Summary 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.
- Published
- 2021