Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury

Abstract

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 =3.18 × 10 –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 = 6.17 × 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. 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.

Machine-learning based MRI radiomics models for early detection of radiation-induced brain injury in nasopharyngeal carcinoma

“…Cerebrovascular injury and remodeling is an underlying hypothesis for the development of RTLI. Recently, a genome-wide association study implicated the genetic susceptibility gene CEP128 in RTLI development [31]. Generally, the particular mechanism of RTLI includes not only demyelination, softening, and necrosis of white matter, but also nerve and glial cell damage caused by direct radiation, which are related to gray matter [32].…”

Cerebral Radiation Necrosis Masquerading as Recurrent, High-Grade Meningioma: A Case Report

“…Although CRN in uenced by various risk factors such as total radiation dose, dose per fraction, treatment duration, irradiated volume, and concurrent use of chemotherapy, the rapidly progressive course of CRN raises the susceptibility of underlying genetic mechanisms (4-7). A prospective cohort study by Wang TM et al in 2019, implicated a radiation injury susceptibility gene (Cep128) as an underlying mechanism of radiationinduced brain injury, as it tightly interacts with multiple radiation-resistant genes (7).…”

“…Recent studies have suggested that immediate, adjuvant RT appears to be strongly associated with improved survival rate of high-grade meningiomas (2,3). CRN is the most relevant side effect after RT and can masquerade as tumor recurrence (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Thus, both establishing an accurate diagnosis and reaching a prompt treatment decisions are challenging.…”

Harnessing genome-wide association studies to minimize adverse radiation-induced side effects

“…Genetic susceptibility studies for radiation-induced central nervous system toxicity are starting to emerge. Wang et al [ 42 ] conducted a three-stage GWAS study with more than 1,000 patients for each stage. Their analysis identified SNPs near the gene CEP128 , which codes a centrosome protein involved in cell cycle progression, and is associated with temporal lobe injury risk (HR=1.45; 95% CI, 1.26–1.66).…”