A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer

被引：1

作者：

Farazi, Manzur ^{[1
]}

Yang, Xin ^{[1
]}

Gehl, Carson J. ^{[1
]}

Barnett, Gillian C. ^{[2
]}

Burnet, Neil G. ^{[3
]}

Chang-Claude, Jenny ^{[4
]}

Parker, Christopher C. ^{[5
]}

Dunning, Alison M. ^{[6
]}

Azria, David ^{[7
]}

Choudhury, Ananya ^{[8
]}

Rancati, Tiziana ^{[9
]}

De Ruysscher, Dirk ^{[10
]}

Seibold, Petra ^{[4
]}

Sperk, Elena ^{[11
]}

Talbot, Christopher J. ^{[12
]}

Veldeman, Liv ^{[13
]}

Webb, Adam J. ^{[12
]}

Elliott, Rebecca ^{[8
]}

Aguado-Barrera, Miguel E. ^{[14
,15
]}

Carballo, Ana M. ^{[14
,16
]}

Fuentes-Rios, Olivia ^{[14
,15
]}

Gomez-Caamano, Antonio ^{[14
,16
]}

Peleteiro, Paula ^{[14
,16
]}

Vega, Ana ^{[14
,15
,17
]}

Ostrer, Harry ^{[18
]}

Rosenstein, Barry S. ^{[19
]}

Saito, Shiro ^{[20
]}

Parliament, Matthew ^{[21
]}

Usmani, Nawaid ^{[21
]}

Marples, Brian ^{[22
]}

Chen, Yuhchyau ^{[22
]}

Morrow, Gary ^{[22
]}

Messing, Edward ^{[22
]}

Janelsins, Michelle C. ^{[22
]}

Hall, William ^{[1
]}

West, Catharine M. L. ^{[8
]}

Auer, Paul L. ^{[1
]}

Kerns, Sarah L. ^{[1
]}

机构：

[1] Med Coll Wisconsin, Milwaukee, WI USA

[2] Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England

[3] Christie NHS Fdn Trust, Manchester, England

[4] German Canc Res Ctr, Heidelberg, Germany

[5] Royal Marsden NHS Fdn Trust, Sutton, England

[6] Univ Cambridge, Cambridge, England

[7] Univ Montpellier, Montpellier Canc Inst ICM, INSERM IRCM U1194, Montpellier, France

[8] Univ Manchester, Manchester, England

[9] Fdn IRCCS Ist Nazl Tumori, Milan, Italy

[10] Maastricht Univ, Med Ctr, GROW Sch, Maastricht, Netherlands

[11] Heidelberg Univ, Univ Med Ctr Mannheim, Med Fac Mannheim, Mannheim Canc Ctr, Mannheim, Germany

[12] Univ Leicester, Leicester, England

[13] Univ Ghent, Ghent Univ Hosp, Ghent, Belgium

[14] Inst Invest Sanitaria Santiago de Compostela, Grp Genet Canc & Enfermedades Raras, Santiago De Compostela, Spain

[15] Fdn Publ Galega Med Xen, Santiago De Compostela, Spain

[16] Hosp Clin Univ Santiago de Compostela, Serv Galego Saude SERGAS, Santiago De Compostela, Spain

[17] Biomed Network Rare Dis CIBERER, Madrid, Spain

[18] Albert Einstein Coll Med, Bronx, NY USA

[19] Icahn Sch Med Mt Sinai, New York, NY USA

[20] Natl Tokyo Med Ctr, Tokyo, Japan

[21] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada

[22] Univ Rochester, Rochester, NY USA

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2025年 / 34卷 / 05期

关键词：

GENOME-WIDE ASSOCIATION; QUALITY-OF-LIFE; RADIATION TOXICITY; GENETIC-VARIANTS; URINARY-BLADDER; METAANALYSIS; DISEASE; REQUITE; TRIAL;

D O I：

10.1158/1055-9965.EPI-24-1228

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：795 / 804

页数：10

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