Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively impacts survivors. Few risk factors are known beyond the radiation dose and volume of bladder exposed. A polygenic risk score (PRS) could identify susceptible patients.
A PRS was built using genome-wide association results from the Radiogenomics Consortium (N=3,988), then tested in the prospective REQUITE and URWCI studies (N=2,034). The primary outcome was time-to-patient-reported gross (≥ grade 2, G2) hematuria analyzed using Cox proportional hazards regression. Secondary outcomes were ≥G2 urinary retention and frequency. The PRS was externally validated for clinically-diagnosed irradiation cystitis in the UK Biobank (N=8,430). A gene-burden test evaluated rare coding variants.
A 115-variant PRS was associated with significantly increased risk of ≥G2 hematuria (hazard ratio [HR] per standard deviation [SD]=1.22, p=0.009) as well as urinary retention (HR-per-SD=1.18, p=0.016) and frequency (HR-per-SD=1.14, p=0.036). When binarized, men in the upper decile (PRShigh) had >2-fold increased risk of hematuria after adjusting for clinical risk factors (HR=2.12, p=0.002; Harrel's c-index 0.71 [95%CI=0.65 to 0.76]). A similar effect size was seen in the UK Biobank for clinically-diagnosed irradiation cystitis (OR=2.15, p=0.026). The burden test identified BOD1L1 as a putative novel radiosensitivity gene.
This PRS identifies susceptible patients and could guide selection of those needing re-optimized treatment plans that spare the bladder beyond currently recommended constraints.
PRS-guided treatment planning in radiation oncology could lower the incidence of clinically relevant bladder toxicity and reduce the impact of this outcome on prostate cancer survivors.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2025 Mar 03 [Epub ahead of print]
Manzur Farazi, Xin Yang, Carson J Gehl, Gillian C Barnett, Neil G Burnet, Jenny Chang-Claude, Christopher C Parker, Alison M Dunning, David Azria, Ananya Choudhury, Tiziana Rancati, Dirk De Ruysscher, Petra Seibold, Elena Sperk, Christopher J Talbot, Liv Veldeman, Adam J Webb, Rebecca Elliott, Miguel E Aguado-Barrera, Ana M Carballo, Olivia Fuentes-Ríos, Antonio Gómez-Caamaño, Paula Peleteiro, Ana Vega, Harry Ostrer, Barry S Rosenstein, Shiro Saito, Matthew Parliament, Nawaid Usmani, Brian Marples, Yuhchyau Chen, Gary Morrow, Edward Messing, Michelle C Janelsins, William Hall, Catharine M L West, Paul L Auer, Sarah Kerns
Medical College of Wisconsin, Milwaukee, WI, United States., Medical College of Wisconsin, Milwaukee, United States., University of Cambridge, Cambridge, United Kingdom., The Christie NHS Foundation Trust, Manchester, United Kingdom., German Cancer Research Center, Heidelberg, Germany., Royal Marsden Hospital, Sutton, Surrey, United Kingdom., Montpellier Cancer Institute, Montpellier, France., University of Manchester, Manchester, United Kingdom., Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy., Maastricht University Medical Centre, Maastricht, Netherlands., Heidelberg University, Mannheim, Germany., University of Leicester, Leicester, United Kingdom., Ghent University Hospital, Ghent, Belgium., Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain., Hospital Clínico Universitario de Santiago de Compostela, Spain., University of Santiago de Compostela, Santiago de Compostela, Spain., Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, A Coruña, Spain., Albert Einstein College of Medicine, United States., Icahn School of Medicine at Mount Sinai, New York, NY, United States., National Tokyo Medical Center, Japan., University of Alberta, Edmonton, Alberta, Canada., University of Rochester Medical Center, Miami, FL, United States., University of Rochester Medical Center, Rochester, NY, United States.