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

Yu, Jiang, University of California, San Francisco; Travis J, Meyers, University of California, San Francisco; Adaeze A, Emeka, Northwestern University Feinberg School of Medicine; Lauren F, Cooley, Northwestern University Feinberg School of Medicine; Philip R, Cooper, Northwestern University Feinberg School of Medicine; Nicola, Lancki, Northwestern University Feinberg School of Medicine; Irene, Helenowski, Northwestern University Feinberg School of Medicine; Linda, Kachuri, University of California, San Francisco; Daniel W, Lin, Fred Hutchinson Cancer Research Center; Janet L, Stanford, Fred Hutchinson Cancer Research Center; Lisa F, Newcomb, Fred Hutchinson Cancer Research Center; Suzanne, Kolb, Fred Hutchinson Cancer Research Center; Antonio, Finelli, Ontario Cancer Institute University of Toronto; Neil E, Fleshner, Ontario Cancer Institute University of Toronto; Maria, Komisarenko, Ontario Cancer Institute University of Toronto; James A, Eastham, Memorial Sloan-Kettering Cancer Center; Behfar, Ehdaie, Memorial Sloan-Kettering Cancer Center; Nicole, Benfante, Memorial Sloan-Kettering Cancer Center; Christopher J, Logothetis, University of Texas MD Anderson Cancer Center; Justin R, Gregg, University of Texas MD Anderson Cancer Center; Cherie A, Perez, University of Texas MD Anderson Cancer Center; Sergio, Garza, University of Texas MD Anderson Cancer Center; Jeri, Kim, University of Texas MD Anderson Cancer Center; Leonard S, Marks, David Geffen School of Medicine at UCLA; Merdie, Delfin, David Geffen School of Medicine at UCLA; Danielle, Barsa, David Geffen School of Medicine at UCLA; Danny, Vesprini, University of Toronto; Laurence H, Klotz, University of Toronto; Andrew, Loblaw, University of Toronto; Alexandre, Mamedov, University of Toronto; Larry S, Goldenberg, The University of British Columbia; Celestia S, Higano, The University of British Columbia; Maria, Spillane, The University of British Columbia; Eugenia, Wu, The University of British Columbia; Ballentine H, Carter, Johns Hopkins School of Medicine; Christian P, Pavlovich, Johns Hopkins School of Medicine; Mufaddal, Mamawala, Johns Hopkins School of Medicine; Tricia, Landis, Johns Hopkins School of Medicine; Peter R, Carroll, University of California, San Francisco; June M, Chan, University of California, San Francisco; Matthew R, Cooperberg, University of California, San Francisco; Janet E, Cowan, University of California, San Francisco; Todd M, Morgan, University of Michigan Medical School; Javed, Siddiqui, University of Michigan Medical School; Rabia, Martin, University of Michigan Medical School; Eric A, Klein, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Karen, Brittain, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Paige, Gotwald, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Daniel A, Barocas, Vanderbilt University Medical Center; Jeremiah R, Dallmer, Vanderbilt University Medical Center; Jennifer B, Gordetsky, Vanderbilt University Medical Center; Pam, Steele, Vanderbilt University Medical Center; Shilajit D, Kundu, Northwestern University Feinberg School of Medicine; Jazmine, Stockdale, Northwestern University Feinberg School of Medicine; Monique J, Roobol, Erasmus MC Cancer Institute; Lionne DF, Venderbos, Erasmus MC Cancer Institute; Martin, Sanda, Emory University; Rebecca, Arnold, Emory University; Dattatraya, Patil, Emory University; Chirstopher P, Evans, University of California, Davis Medical Center, Sacramento; Marc A, Dall'Era, University of California, Davis Medical Center, Sacramento; Anjali, Vij, University of California, Davis Medical Center, Sacramento; Anthony J, Costello, Royal Melbourne Hospital; Ken, Chow, Royal Melbourne Hospital; Niall M, Corcoran, Royal Melbourne Hospital; Soroush, Rais-Bahrami, The University of Alabama at Birmingham; Courtney, Phares, The University of Alabama at Birmingham; Douglas S, Scherr, New York Presbyterian Hospital; Thomas, Flynn, New York Presbyterian Hospital; Jeffrey R, Karnes, Mayo Clinic Education and Research; Michael, Koch, Indiana University School of Medicine; Courtney Rose, Dhondt, Indiana University School of Medicine; Joel B, Nelson, University of Pittsburgh School of Medicine; Dawn, McBride, University of Pittsburgh School of Medicine; Michael S, Cookson, University of Oklahoma Health Sciences Center; Kelly L, Stratton, University of Oklahoma Health Sciences Center; Stephen, Farriester, University of Oklahoma Health Sciences Center; Erin, Hemken, University of Oklahoma Health Sciences Center; Walter M, Stadler, The University of Chicago; Tuula, Pera, The University of Chicago; Deimante, Banionyte, The University of Chicago; Fernando J, Bianco, Urological Research Network; Isabel H, Lopez, Urological Research Network; Stacy, Loeb, NYU Langone Health; Samir S, Taneja, NYU Langone Health; Nataliya, Byrne, NYU Langone Health; Christopher L, Amling, Oregon Health and Science University; Ann, Martinez, Oregon Health and Science University; Luc, Boileau, Oregon Health and Science University; Franklin D, Gaylis, University of California, San Diego; Jacqueline, Petkewicz, NorthShore University HealthSystem; Nicholas, Kirwen, NorthShore University HealthSystem; Brian T, Helfand, NorthShore University HealthSystem; Jianfeng, Xu, NorthShore University HealthSystem; Denise M, Scholtens, Northwestern University Feinberg School of Medicine; William J, Catalona, Northwestern University Feinberg School of Medicine; John, Witte, University of California, San Francisco

Publication

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

Persistent URL

https://open.library.emory.edu/purl/378tb2rcn5-emory

Last modified

05/22/2025

Type of Material

Article

Authors

Yu Jiang, University of California, San Francisco

Travis J Meyers, University of California, San Francisco

Adaeze A Emeka, Northwestern University Feinberg School of Medicine

Lauren F Cooley, Northwestern University Feinberg School of Medicine

Philip R Cooper, Northwestern University Feinberg School of Medicine

Nicola Lancki, Northwestern University Feinberg School of MedicineIrene Helenowski, Northwestern University Feinberg School of MedicineLinda Kachuri, University of California, San FranciscoDaniel W Lin, Fred Hutchinson Cancer Research CenterJanet L Stanford, Fred Hutchinson Cancer Research CenterLisa F Newcomb, Fred Hutchinson Cancer Research CenterSuzanne Kolb, Fred Hutchinson Cancer Research CenterAntonio Finelli, Ontario Cancer Institute University of TorontoNeil E Fleshner, Ontario Cancer Institute University of TorontoMaria Komisarenko, Ontario Cancer Institute University of TorontoJames A Eastham, Memorial Sloan-Kettering Cancer CenterBehfar Ehdaie, Memorial Sloan-Kettering Cancer CenterNicole Benfante, Memorial Sloan-Kettering Cancer CenterChristopher J Logothetis, University of Texas MD Anderson Cancer CenterJustin R Gregg, University of Texas MD Anderson Cancer CenterCherie A Perez, University of Texas MD Anderson Cancer CenterSergio Garza, University of Texas MD Anderson Cancer CenterJeri Kim, University of Texas MD Anderson Cancer CenterLeonard S Marks, David Geffen School of Medicine at UCLAMerdie Delfin, David Geffen School of Medicine at UCLADanielle Barsa, David Geffen School of Medicine at UCLADanny Vesprini, University of TorontoLaurence H Klotz, University of TorontoAndrew Loblaw, University of TorontoAlexandre Mamedov, University of TorontoLarry S Goldenberg, The University of British ColumbiaCelestia S Higano, The University of British ColumbiaMaria Spillane, The University of British ColumbiaEugenia Wu, The University of British ColumbiaBallentine H Carter, Johns Hopkins School of MedicineChristian P Pavlovich, Johns Hopkins School of MedicineMufaddal Mamawala, Johns Hopkins School of MedicineTricia Landis, Johns Hopkins School of MedicinePeter R Carroll, University of California, San FranciscoJune M Chan, University of California, San FranciscoMatthew R Cooperberg, University of California, San FranciscoJanet E Cowan, University of California, San FranciscoTodd M Morgan, University of Michigan Medical SchoolJaved Siddiqui, University of Michigan Medical SchoolRabia Martin, University of Michigan Medical SchoolEric A Klein, Cleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityKaren Brittain, Cleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityPaige Gotwald, Cleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityDaniel A Barocas, Vanderbilt University Medical CenterJeremiah R Dallmer, Vanderbilt University Medical CenterJennifer B Gordetsky, Vanderbilt University Medical CenterPam Steele, Vanderbilt University Medical CenterShilajit D Kundu, Northwestern University Feinberg School of MedicineJazmine Stockdale, Northwestern University Feinberg School of MedicineMonique J Roobol, Erasmus MC Cancer InstituteLionne DF Venderbos, Erasmus MC Cancer InstituteMartin Sanda, Emory UniversityRebecca Arnold, Emory UniversityDattatraya Patil, Emory UniversityChirstopher P Evans, University of California, Davis Medical Center, SacramentoMarc A Dall'Era, University of California, Davis Medical Center, SacramentoAnjali Vij, University of California, Davis Medical Center, SacramentoAnthony J Costello, Royal Melbourne HospitalKen Chow, Royal Melbourne HospitalNiall M Corcoran, Royal Melbourne HospitalSoroush Rais-Bahrami, The University of Alabama at BirminghamCourtney Phares, The University of Alabama at BirminghamDouglas S Scherr, New York Presbyterian HospitalThomas Flynn, New York Presbyterian HospitalJeffrey R Karnes, Mayo Clinic Education and ResearchMichael Koch, Indiana University School of MedicineCourtney Rose Dhondt, Indiana University School of MedicineJoel B Nelson, University of Pittsburgh School of MedicineDawn McBride, University of Pittsburgh School of MedicineMichael S Cookson, University of Oklahoma Health Sciences CenterKelly L Stratton, University of Oklahoma Health Sciences CenterStephen Farriester, University of Oklahoma Health Sciences CenterErin Hemken, University of Oklahoma Health Sciences CenterWalter M Stadler, The University of ChicagoTuula Pera, The University of ChicagoDeimante Banionyte, The University of ChicagoFernando J Bianco, Urological Research NetworkIsabel H Lopez, Urological Research NetworkStacy Loeb, NYU Langone HealthSamir S Taneja, NYU Langone HealthNataliya Byrne, NYU Langone HealthChristopher L Amling, Oregon Health and Science UniversityAnn Martinez, Oregon Health and Science UniversityLuc Boileau, Oregon Health and Science UniversityFranklin D Gaylis, University of California, San DiegoJacqueline Petkewicz, NorthShore University HealthSystemNicholas Kirwen, NorthShore University HealthSystemBrian T Helfand, NorthShore University HealthSystemJianfeng Xu, NorthShore University HealthSystemDenise M Scholtens, Northwestern University Feinberg School of MedicineWilliam J Catalona, Northwestern University Feinberg School of MedicineJohn Witte, University of California, San Francisco

Language

English

Date

2022-01-13

Publisher

Elsevier

Publication Version

Final Published Version

Copyright Statement

License

Creative Commons Attribution 4.0 International

Final Published Version (URL)

http://dx.doi.org/10.1016/j.xhgg.2021.100070

Title of Journal or Parent Work

Human Genetics and Genomics Advances

Volume

Issue

Grant/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.

Supplemental Material (URL)

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.

Author Notes

John S. Witte, jswitte@stanford.edu

Keywords

Research Categories

Health Sciences, Epidemiology
Health Sciences, Oncology

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