期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 111, 期 6, 页码 620-628出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djy150
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资金
- National Key Research and Development Program of China [2016YFC1302704, 2016YFC0902001]
- Sino-Sweden Joint Research Programme [81861138006]
- Science and Technology Planning Project of Guangzhou, China [201804020094]
- Special Support Program for High-level Professionals on Scientific and Technological Innovation of Guangdong Province, China [2014TX01R201]
- Health & Medical Collaborative Innovation Project of Guangzhou City, China [201604020003]
- Key Project for International Cooperation and Exchange of the National Natural Science Foundation of China [81220108022]
- National Science Fund for Distinguished Young Scholars of China [81325018]
- National High Technology Research and Development Program of China (the 863 Program) [2012AA02A206]
- Science and Technology Planning Project of Guangdong Province, China [2011B031800218]
- National Natural Science Foundation of China [81201747, 81372882, 81572781]
- Natural Science Foundation of Guangdong Province, China [S2012040006323, 2014A030313023]
- Open Foundation of State Key Laboratory of Oncology in South China [HN2013-07]
Background Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. Methods We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. Results We identified a promoter variant rs17111237 (A>G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, P-combined=3.18x10(-7)) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF=0.18, R-2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, P-combined= 6.17x10(-9)). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A>G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P<.001) were enriched in the neurogenesis pathway. Conclusions This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.
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