journal contribution
posted on 2025-05-02, 07:40 authored by 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 L. Kerns Figure S1 shows principal components analysis of participants from the RGC and REQUITE+URWCI cohorts.
Funding
National Institutes of Health (NIH)
European Commission (EC)
Movember Canada (MVC)
U.S. Department of Defense (DOD)
Cancer Research UK Cambridge Institute, University of Cambridge (CRUK CI)
Cancer Research UK Manchester Centre (MCRC)
European Regional Development Fund (ERDF)
History
ARTICLE ABSTRACT
Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively affects 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) and 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 a significantly increased risk of ≥G2 hematuria [hazard ratio (HR) per 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 a >2-fold increased risk of hematuria after adjusting for clinical risk factors [HR = 2.12; P = 0.002; Harrel’s concordance index = 0.71 (95% confidence interval, 0.65–0.76)]. A similar effect size was seen in the UK Biobank for clinically diagnosed irradiation cystitis [odds ratio (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 the selection of those needing reoptimized 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.
