Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis

Autor:	Jiang-Bo Zhang, Yong-Qiao He, Wen-Qiong Xue, Wei Hua Jia, Ming-Yuan Chen, Xiao-Hui Zheng, Shen Guoping, Shao-Dan Zhang, Ye-Zhu Hu, Tong-Min Wang, Ruo-Wen Xiao, Ying Sun, Xi-Zhao Li, Da-Wei Yang, Pei-Fen Zhang
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Oncology medicine.medical_specialty Genome-wide association study Radiogenomics lcsh:Medicine Biology Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Functional mapping Oral mucositis 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Mucositis Genetic predisposition Humans Genetic Predisposition to Disease Radiation injuries Gene Stomatitis Nasopharyngeal Carcinoma Research lcsh:R Nasopharyngeal Neoplasms General Medicine medicine.disease Genetic architecture 030104 developmental biology Nasopharyngeal carcinoma 030220 oncology & carcinogenesis Expression quantitative trait loci
Zdroj:	Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-12 (2020) Journal of Translational Medicine
ISSN:	1479-5876
Popis:	Background Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy. Methods A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes. Results We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10–6.57; P = 6.33 × 10−6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10−7). Conclusions These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.
Databáze:	OpenAIRE
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