| Title: | A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer. |
| Journal: | Cancer Epidemiology Biomarkers & Prevention |
| Published: | 3 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40029246/ |
| DOI: | https://doi.org/10.1158/1055-9965.epi-24-1228 |
Publication 15998
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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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
15 Keywords
- Aged
- Cystitis
- Genetic Risk Score
- Genome-Wide Association Study
- Hematuria
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Prospective Studies
- Prostatic Neoplasms
- Radiation Injuries
- Radiotherapy
- Risk Factors
- Urinary Bladder
38 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 90542 | Genomic modeling of radiation toxicity |
Enabling scientific discoveries that improve human health