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- Title
Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.
- Authors
Wang, Tong-Min; Shen, Guo-Ping; Chen, Ming-Yuan; Zhang, Jiang-Bo; Sun, Ying; He, Jing; Xue, Wen-Qiong; Li, Xi-Zhao; Huang, Shao-Yi; Zheng, Xiao-Hui; Zhang, Shao-Dan; Hu, Ye-Zhu; Qin, Hai-De; Bei, Jin-Xin; Ma, Jun; Mu, Jianbing; Shugart, Yin Yao; Jia, Wei-Hua; Yao Shugart, Yin
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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, Pcombined=3.18 × 10-7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, Pcombined= 6.17 × 10-9). 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.<bold>Conclusions: </bold>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.
- Subjects
RADIATION injuries; BRAIN injuries; LYMPHOBLASTOID cell lines
- Publication
JNCI: Journal of the National Cancer Institute, 2019, Vol 111, Issue 6, p620
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djy150