Journal Article

DKFZ-2025-00477

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer.

Farazi, M. ; Yang, X. ; Gehl, C. J. ; Barnett, G. C. ; Burnet, N. G. ; Chang-Claude, J.DKFZ* ; Parker, C. C. ; Dunning, A. M. ; Azria, D. ; Choudhury, A. ; Rancati, T. ; De Ruysscher, D. ; Seibold, P.DKFZ* ; Sperk, E. ; Talbot, C. J. ; Veldeman, L. ; Webb, A. J. ; Elliott, R. ; Aguado-Barrera, M. E. ; Carballo, A. M. ; Fuentes-Ríos, O. ; Gómez-Caamaño, A. ; Peleteiro, P. ; Vega, A. ; Ostrer, H. ; Rosenstein, B. S. ; Saito, S. ; Parliament, M. ; Usmani, N. ; Marples, B. ; Chen, Y. ; Morrow, G. ; Messing, E. ; Janelsins, M. C. ; Hall, W. ; West, C. M. L. ; Auer, P. L. ; Kerns, S.

2025
AACR Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/1055-9965.EPI-24-1228

Abstract: 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.

Note: 2025 May 2;34(5):795-804

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Contributing Institute(s):

1. Epidemiologie von Krebs (C020)
2. Personalisierte Früherkennung des Prostatakarzinoms (C130)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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