Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

Yu Jiang^{1

2}, Travis J Meyers^{1

2}, Adaeze A Emeka³, Lauren Folgosa Cooley³, Phillip R Cooper³, Nicola Lancki⁴, Irene Helenowski⁴, Linda Kachuri¹, Daniel W Lin^{5

6}, Janet L Stanford^{7

8}, Lisa F Newcomb^{5

6}, Suzanne Kolb^{7

8}, Antonio Finelli⁹, Neil E Fleshner⁹, Maria Komisarenko⁹, James A Eastham¹⁰, Behfar Ehdaie¹⁰, Nicole Benfante¹⁰, Christopher J Logothetis¹¹, Justin R Gregg¹¹, Cherie A Perez¹¹, Sergio Garza¹¹, Jeri Kim¹¹, Leonard S Marks¹², Merdie Delfin¹², Danielle Barsa¹², Danny Vesprini¹³, Laurence H Klotz¹³, Andrew Loblaw¹³, Alexandre Mamedov¹³, S Larry Goldenberg¹⁴, Celestia S Higano¹⁴, Maria Spillane¹⁴, Eugenia Wu¹⁴, H Ballentine Carter¹⁵, Christian P Pavlovich¹⁵, Mufaddal Mamawala¹⁵, Tricia Landis¹⁵, Peter R Carroll¹⁶, June M Chan^{1

16}, Matthew R Cooperberg^{16

17}, Janet E Cowan¹⁶, Todd M Morgan¹⁸, Javed Siddiqui¹⁹, Rabia Martin¹⁹, Eric A Klein²⁰, Karen Brittain²⁰, Paige Gotwald²⁰, Daniel A Barocas²¹, Jeremiah R Dallmer^{21

22}, Jennifer B Gordetsky^{21

23}, Pam Steele²¹, Shilajit D Kundu³, Jazmine Stockdale³, Monique J Roobol²⁴, Lionne D F Venderbos²⁴, Martin G Sanda²⁵, Rebecca Arnold²⁵, Dattatraya Patil²⁵, Christopher P Evans²⁶, Marc A Dall'Era²⁶, Anjali Vij²⁶, Anthony J Costello²⁷, Ken Chow²⁷, Niall M Corcoran²⁷, Soroush Rais-Bahrami^{28

29}, Courtney Phares²⁸, Douglas S Scherr³⁰, Thomas Flynn³⁰, R Jeffrey Karnes³¹, Michael Koch³², Courtney Rose Dhondt³², Joel B Nelson³³, Dawn McBride³³, Michael S Cookson³⁴, Kelly L Stratton³⁴, Stephen Farriester³⁴, Erin Hemken³⁴, Walter M Stadler³⁵, Tuula Pera³⁵, Deimante Banionyte³⁵, Fernando J Bianco Jr³⁶, Isabel H Lopez³⁶, Stacy Loeb³⁷, Samir S Taneja³⁷, Nataliya Byrne³⁷, Christopher L Amling³⁸, Ann Martinez³⁸, Luc Boileau³⁸, Franklin D Gaylis³⁹, Jacqueline Petkewicz⁴⁰, Nicholas Kirwen⁴⁰, Brian T Helfand⁴⁰, Jianfeng Xu⁴⁰, Denise M Scholtens⁴, William J Catalona^{3

41}, John S Witte^{1

16

17

42

41}

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
² These authors contributed equally to the first authorship.
³ Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Public Health Sciences, Seattle, WA 98109, USA.
⁶ Department of Urology, University of Washington, Seattle 98195, WA, USA.
⁷ Fred Hutchinson Cancer Research Center, Cancer Epidemiology Program, Public Health Sciences, Seattle, WA 98109, USA.
⁸ Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA 98195, USA.
⁹ Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
¹⁰ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Departments of Genitourinary Medical Oncology and Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
¹² Department of Urology, David Geffen School of Medicine at UCLA, USA.
¹³ Odette Cancer Centre, Sunnybrook Health and Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
¹⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Department of Urology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, USA.
²¹ Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²³ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁴ Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
²⁵ Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
²⁶ Department of Urologic Surgery, University of California, Davis Medical Center, Sacramento, CA, USA.
²⁷ Department of Urology, Royal Melbourne Hospital and University of Melbourne, Australia.
²⁸ Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁹ Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
³⁰ Department of Urology, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
³¹ Mayo Clinic Department of Urology, Rochester, MN, USA.
³² Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
³³ Department of Urology, University of Pittsburgh School of Medicine, PA, USA.
³⁴ Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁵ University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.
³⁶ Urological Research Network, Miami Lakes, FL, USA.
³⁷ Departments of Urology and Population Health, New York University Langone Health and Manhattan Veterans Affairs Medical Center, New York, NY, USA.
³⁸ Department of Urology, Oregon Health and Science University, Portland, OR, USA.
³⁹ Genesis Healthcare Partners, Department of Urology, University of California, San Diego, CA, USA.
⁴⁰ Division of Urology, NorthShore University Health System, Evanston, IL, USA.
⁴¹ These authors contributed equally to the senior authorship.
⁴² Departments of Epidemiology and Population Health, Biomedical Data Science, and Genetics, Stanford University, Stanford, CA, USA.

PMID: 34993496
PMCID: PMC8725988
DOI: 10.1016/j.xhgg.2021.100070

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

Yu Jiang et al. HGG Adv. 2022.

. 2022 Jan 13;3(1):100070.

doi: 10.1016/j.xhgg.2021.100070. Epub 2021 Nov 19.

Authors

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
² These authors contributed equally to the first authorship.
³ Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Public Health Sciences, Seattle, WA 98109, USA.
⁶ Department of Urology, University of Washington, Seattle 98195, WA, USA.
⁷ Fred Hutchinson Cancer Research Center, Cancer Epidemiology Program, Public Health Sciences, Seattle, WA 98109, USA.
⁸ Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA 98195, USA.
⁹ Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
¹⁰ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Departments of Genitourinary Medical Oncology and Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
¹² Department of Urology, David Geffen School of Medicine at UCLA, USA.
¹³ Odette Cancer Centre, Sunnybrook Health and Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
¹⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Department of Urology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, USA.
²¹ Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²³ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁴ Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
²⁵ Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
²⁶ Department of Urologic Surgery, University of California, Davis Medical Center, Sacramento, CA, USA.
²⁷ Department of Urology, Royal Melbourne Hospital and University of Melbourne, Australia.
²⁸ Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁹ Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
³⁰ Department of Urology, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
³¹ Mayo Clinic Department of Urology, Rochester, MN, USA.
³² Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
³³ Department of Urology, University of Pittsburgh School of Medicine, PA, USA.
³⁴ Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁵ University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.
³⁶ Urological Research Network, Miami Lakes, FL, USA.
³⁷ Departments of Urology and Population Health, New York University Langone Health and Manhattan Veterans Affairs Medical Center, New York, NY, USA.
³⁸ Department of Urology, Oregon Health and Science University, Portland, OR, USA.
³⁹ Genesis Healthcare Partners, Department of Urology, University of California, San Diego, CA, USA.
⁴⁰ Division of Urology, NorthShore University Health System, Evanston, IL, USA.
⁴¹ These authors contributed equally to the senior authorship.
⁴² Departments of Epidemiology and Population Health, Biomedical Data Science, and Genetics, Stanford University, Stanford, CA, USA.

PMID: 34993496
PMCID: PMC8725988
DOI: 10.1016/j.xhgg.2021.100070

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 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 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.

Keywords: genetics; genome-wide association study; prostate; prostatic neoplasms.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1**
Flow chart highlighting the approach and samples used in the genome-wide association analysis First, we undertook a discovery GWAS in men of European ancestry. Fourteen variants were associated with conversion (p < 5 × 10⁻⁸). All variants were evaluated for replication in the replication cohorts alone and then in a meta-analysis combining the discovery and replication cohorts. Four additional variants reached statistical significance in the combined meta-analysis (p < 5 × 10⁻⁸).

**Figure 2**
Results from the GWASs of conversion from AS to treatment (A) in 5,222 prostate cancer (PC) patients of European ancestry; and (B) in discovery and replication cohorts. p values are for variant associations with conversion, adjusted for age and 10 ancestry principal components using Cox proportional hazards models. Blue dashed line denotes the genome-wide significance threshold. Orange peaks indicate genome-wide significant hits (p < 5 × 10⁻⁸). The top variants in each chromosome are annotated with their rsID.

**Figure 3**
Association between time to conversion from AS to treatment (A) with the PC genetic risk score (GRS); and (B) with the prostate-specific antigen (PSA) GRS. The fifth and sixth deciles of PC GRSs are used as the reference. Bars indicate 95% confidence intervals (CIs) around the hazard ratio (HR) estimates. The minimally adjusted model includes age and the first 10 genetic principal components. The fully adjusted model also includes Gleason grade group (GG1, GG2, or ≥GG3), PSA concentration (ng/mL), clinical stage (cT1, cT2, or cT3/cT4), and number of positive biopsy cores (1–2, 3, or ≥4).

**Figure 4**
Kaplan-Meier plots of active surveillance conversion-free probability for low, intermediate, and high clinicopathological risk categories The plots are stratified by the top and bottom deciles of GRSs for PC (GRS_PC, A) and for PSA levels (GRS_PSA, B). The curves within each risk category are compared between the top and bottom GRS deciles using a log-rank test (p values given next to corresponding curves).

See this image and copyright information in PMC

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Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

Affiliations

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous