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A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer. Cancer Epidemiol Biomarkers Prev 2025 May 02;34(5):795-804

Date

03/03/2025

Pubmed ID

40029246

Pubmed Central ID

PMC12048210

DOI

10.1158/1055-9965.EPI-24-1228

Scopus ID

2-s2.0-105004381541 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: This PRS identifies susceptible patients and could guide the selection of those needing reoptimized treatment plans that spare the bladder beyond currently recommended constraints.

IMPACT: 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.

Author List

Farazi M, Yang X, Gehl CJ, Barnett GC, Burnet NG, Chang-Claude J, Parker CC, Dunning AM, Azria D, Choudhury A, Rancati T, De Ruysscher D, Seibold P, Sperk E, Talbot CJ, Veldeman L, Webb AJ, Elliott R, Aguado-Barrera ME, Carballo AM, Fuentes-Ríos O, Gómez-Caamaño A, Peleteiro P, Vega A, Ostrer H, Rosenstein BS, Saito S, Parliament M, Usmani N, Marples B, Chen Y, Morrow G, Messing E, Janelsins MC, Hall W, West CML, Auer PL, Kerns SL

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Manzur Rahman Farazi Statistical Research Scientist II in the Data Science Institute department at Medical College of Wisconsin
William Adrian Hall MD Chair, Professor in the Radiation Oncology department at Medical College of Wisconsin
Sarah L. Kerns PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aged
Cystitis
Genome-Wide Association Study
Hematuria
Humans
Male
Middle Aged
Multifactorial Inheritance
Prospective Studies
Prostatic Neoplasms
Radiation Injuries
Radiotherapy
Risk Factors
Urinary Bladder