期刊
EBIOMEDICINE
卷 10, 期 -, 页码 150-163出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2016.07.022
关键词
Radiogenomics; Genome-wide association study; Prostate cancer; Radiation toxicity; Cancer survivorship; Quality of life
资金
- Cancer Research UK [C1094/A11728, C26900/A8740, C8197/A10865, C8197/A10123]
- Royal College of Radiologists [C26900/ A8740]
- National Institute for Health Research
- Addenbrooke's Charitable Trust
- Institute of Cancer Research (National Institute for Health Research) Biomedical Research Centre [C46/A2131]
- National Institute for Health Research Cambridge Biomedical Research Centre
- UK Medical Research Council [RG70550]
- Joseph Mitchell Trust
- Experimental Cancer Medicine Centre
- Cancer Research UK Program grant Section of Radiotherapy [C33589/ A19727]
- United States National Institutes of Health [1R01CA134444, 2P30CA014520-34, 1K07CA187546-01A1]
- American Cancer Society [RSGT-05-200-01-CCE]
- U.S. Department of Defense [PC074201]
- Mount Sinai Tisch Cancer Institute Developmental Fund Award
- Instituto de Salud Carlos III [FIS PI10/00164, PI13/02030, PI13/01136]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Xunta de Galicia
- European Social Fund [POS-A/2013/034]
- Alberta Cancer Board Research Initiative Program [103.0393.71760001404]
- European Union [601826]
- Manchester Experimental Cancer Medicine Centre
- UK Medical Research Council
- Department of Health and Cancer Research UK [CRUK/06/016, C8262/A7253]
- NHS
- Cancer Research UK [10588, 7253, 19727, 16565, 18504] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124] Funding Source: researchfish
- Medical Research Council [MC_UU_12023/28, 1366822, MC_UU_12023/6, MC_U122861330] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10106] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10119] Funding Source: researchfish
- MRC [MC_UU_12023/6, MC_UU_12023/28, MC_U122861330] Funding Source: UKRI
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 x 10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value = 3.21 x 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. (C) 2016 The Authors. Published by Elsevier B.V.
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