@article{04c5035437c347fd945d2f9e762565ee,
title = "Radiogenomics consortium genome-wide association study meta-analysis of late toxicity after prostate cancer radiotherapy",
abstract = "Background: A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. Methods: We conducted an individual patient data meta-analysis of six genome-wide association studies (n ¼ 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 108 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n ¼ 962). All statistical tests were two-sided. Results: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta ¼ 6.2 1010), rs10969913 with decreased urinary stream (Pmeta ¼ 2.9 1010), and rs11122573 with hematuria (Pmeta ¼ 1.8 108). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional ¼ 4.7 106). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. Conclusions: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.",
author = "{Radiogenomics Consortium} and Kerns, {Sarah L.} and Laura Fachal and Leila Dorling and Barnett, {Gillian C.} and Andrea Baran and Peterson, {Derick R.} and Michelle Hollenberg and Ke Hao and {Di Narzo}, Antonio and Ahsen, {Mehmet Eren} and Gaurav Pandey and Bentzen, {S{\o}ren M.} and Michelle Janelsins and Elliott, {Rebecca M.} and Pharoah, {Paul D.P.} and Burnet, {Neil G.} and Dearnaley, {David P.} and Gulliford, {Sarah L.} and Emma Hall and Sydes, {Matthew R.} and Aguado-Barrera, {Miguel E.} and {Gomez-Caama {\~n}o}, Antonio and Carballo, {Ana M.} and Paula Peleteiro and Ramon Lobato-Busto and Richard Stock and Stone, {Nelson N.} and Harry Ostrer and Nawaid Usmani and Sandeep Singhal and Hiroshi Tsuji and Takashi Imai and Shiro Saito and Rosalind Eeles and Kim DeRuyck and Matthew Parliament and Dunning, {Alison M.} and Ana Vega and Rosenstein, {Barry S.} and West, {Catharine M.L.}",
note = "Funding Information: This work was supported by the US National Institutes of Health (NIH; K07 CA187546 to SLK; SBIR HHSN261201500043C to BSR), the United States Department of Defense (PC140371 to BSR and HO), and the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 656144. Genotyping via the OncoArray was funded by the NIH (U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility [ELLIPSE] project and X01HG007492 to the Center for Inherited Disease Research [CIDR] under contract number HHSN268201200008I) as well as C8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). RAPPER was Funding Information: supported by Cancer Research UK grants C1094/A18504, C147/A25254, and C147/A25254 and NIHR Manchester Biomedical Research Centre funding. The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135; European Commission{\textquoteright}s Seventh Framework Programme grant agreement No. 223175 (HEALTH-F2-2009–223175); and the NIH Cancer Post-Cancer GWAS initiative grant: 1U19 CA 148537–01 (the GAME-ON initiative). CMLW is supported by the NIHR Manchester Biomedical Research Centre and the EU{\textquoteright}s 7th Framework Programme Grant Agreement No 601826. GP and MEA{\textquoteright}s work was also partially supported by NIH grant R01GM114434. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT15/00070, INT16/00154, INT17/00133; PI16/00046; PI13/ 02030; PI10/00164), and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B) given to AV. DPD was supported by the NIHR Royal Marsden Hospital and Institute of Cancer Research Biomedical Research Centre. Publisher Copyright: {\textcopyright} The Author(s) 2019. Published by Oxford University Press. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2020",
doi = "10.1093/JNCI/DJZ075",
language = "English (US)",
volume = "112",
pages = "179--190",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "2",
}