Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.
Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.
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DOI：
10.1016/j.ebiom.2016.07.022
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发表时间：
2016-08
期刊：
影响因子：
11.1
通讯作者：
West, Catharine M. L.
中科院分区：
文献类型：
--
作者：
Kerns, Sarah L.;Dorling, Leila;Fachal, Laura;Bentzen, Soren;Pharoah, Paul D. P.;Barnes, Daniel R.;Gomez-Caamano, Antonio;Carballo, Ana M.;Dearnaley, David P.;Peleteiro, Paula;Gulliford, Sarah L.;Hall, Emma;Michailidou, Kyriaki;Carracedo, Angel;Sia, Michael;Stock, Richard;Stone, Nelson N.;Sydes, Matthew R.;Tyrer, Jonathan P.;Ahmed, Shahana;Parliament, Matthew;Ostrer, Harry;Rosenstein, Barry S.;Vega, Ana;Burnet, Neil G.;Dunning, Alison M.;Barnett, Gillian C.;West, Catharine M. L.
关键词：
近50%的癌症患者接受放疗。晚期放疗毒性影响长期癌症幸存者的生活质量，少数患者的副作用风险限制了大多数患者的处方剂量。开发一种预测毒性风险的测试可能会使许多癌症患者受益。我们的目的是荟萃分析来自前列腺癌放疗队列的四项全基因组关联研究的个体水平数据，包括1564名男性，以确定毒性的遗传标志物。使用多变量回归，调整临床和患者相关风险因素，对普罗维登评估的两年毒性终点（尿频、尿流减少、直肠出血、总体毒性）和单核苷酸多态性（SNP）相关性进行了检验。一项固定效应荟萃分析确定了两个SNP：5q31.2上的rs17599026伴尿频（比值比[OR] 3.12，95%置信区间[CI] 2.08 - 4.69，p值4.16 × 10 − 8）和rs7720298在5p15.2伴尿流减少（OR 2.71，95% CI 1.90 - 3.86，p值= 3.21 × 10 − 8）。这些SNP位于在盆腔放疗不利影响的组织中表达的基因内，包括膀胱、肾脏、直肠和小肠。结果表明，异质性放疗队列可以结合起来，以确定新的中度遗传变异与放疗毒性。这项工作为更大规模的合作努力提供了基础，以确定未来涉及多基因风险分析的测试的足够变异。SNPs rs17599026和rs7720298增加前列腺癌患者放疗后尿毒性的风险。可以对来自异质性放疗队列的数据进行荟萃分析，以识别与毒性相关的遗传变异。基于SNP的预测分析可以提高放射治疗的治疗指数，并有助于癌症治疗的个体化。少数人放射治疗副作用的风险限制了大多数人的剂量。需要一种测试来预测风险，以便个性化治疗。最近对几百名患者进行的全基因组研究发现，没有或只有一种遗传变异会增加副作用的风险。需要进行更大规模的研究，但很困难，因为不同中心的治疗方法不同。我们对来自四个中心的> 1500名前列腺癌患者的研究发现了两种变异。该研究表明，将异构放射治疗数据集结合起来，并进行更大的合作努力，为未来的测试确定足够的变体是值得的。由于近50%的癌症患者接受放射治疗，我们的工作可以使许多人受益。
Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling. SNPs rs17599026 and rs7720298 increase risk of urinary toxicity following radiotherapy in prostate cancer patients. Data from heterogeneous radiotherapy cohorts can be meta-analyzed to identify genetic variants associated with toxicity. A SNP-based predictive assay could improve the therapeutic index of radiotherapy and aid in individualization of cancer treatment. Risk of radiotherapy side-effects in a minority limits doses given to the majority. A test is needed to predict risks so treatments are personalized. Recent whole-genome studies in a few hundred patients found none or one genetic variant increasing side-effect risk. Larger studies are needed, but difficult because treatments differ between centers. Our study of > 1500 prostate cancer patients from four centers found two variants. The research shows combining heterogeneous radiotherapy datasets works and larger collaborative efforts identifying enough variants for a future test are worthwhile. As nearly 50% of cancer patients have radiotherapy, our work could benefit many people.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
DOI：
10.1016/j.ijrobp.2009.09.040
发表时间：
2010-03-01
影响因子：
7
作者：
Bentzen, Soren M.;Constine, Louis S.;Deasy, Joseph O.;Eisbruch, Avi;Jackson, Andrew;Marks, Lawrence B.;Ten Haken, Randall K.;Yorke, Ellen D.
通讯作者：
Yorke, Ellen D.