Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury
| Autor: | Jiang Bo Zhang, Guo Ping Shen, Shao Dan Zhang, Tong-Min Wang, Xi Zhao Li, Jun Ma, Ying Sun, Ming Yuan Chen, Wen Qiong Xue, Jing He, Jin Xin Bei, Xiao Hui Zheng, Yin Yao Shugart, Ye Zhu Hu, Hai De Qin, Shao Yi Huang, Jianbing Mu, Wei Hua Jia |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Linkage disequilibrium Genome-wide association study Single-nucleotide polymorphism Cohort Studies 03 medical and health sciences 0302 clinical medicine Internal medicine Genetic predisposition medicine Humans Genetic Predisposition to Disease Promoter Regions Genetic Radiation Injuries Allele frequency Genetic association Nasopharyngeal Carcinoma business.industry Hazard ratio Nasopharyngeal Neoplasms Articles Middle Aged Temporal Lobe Minor allele frequency HEK293 Cells 030220 oncology & carcinogenesis Brain Injuries Female business Genome-Wide Association Study |
| Zdroj: | JNCI Journal of the National Cancer Institute |
| ISSN: | 1460-2105 0027-8874 |
| Popis: | 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, 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 |
| Databáze: | OpenAIRE |
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