A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer.
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Farazi Manzur, Yang Xin, Gehl Carson J, Barnett Gillian C, Burnet Neil G, Chang-Claude Jenny, Parker Christopher C, Dunning Alison M, Azria David, Choudhury Ananya, Rancati Tiziana, De Ruysscher Dirk, Seibold Petra, Sperk Elena, Talbot Christopher J, Veldeman Liv, Webb Adam J, Elliott Rebecca, Aguado-Barrera Miguel E, Carballo Ana M, Fuentes-Ríos Olivia, Gómez-Caamaño Antonio, Peleteiro Paula, Vega Ana, Ostrer Harry, Rosenstein Barry S, Saito Shiro, Parliament Matthew, Usmani Nawaid, Marples Brian, Chen Yuhchyau, Morrow Gary, Messing Edward, Janelsins Michelle C, Hall William, West Catharine M L, Auer Paul L, Kerns Sarah L
Аннотация
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.