Yang Da-Wei, Wang Tong-Min, Zhang Jiang-Bo, Li Xi-Zhao, He Yong-Qiao, Xiao Ruowen, Xue Wen-Qiong, Zheng Xiao-Hui, Zhang Pei-Fen, Zhang Shao-Dan, Hu Ye-Zhu, Shen Guo-Ping, Chen Mingyuan, Sun Ying, Jia Wei-Hua
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China.
J Transl Med. 2020 Jun 5;18(1):224. doi: 10.1186/s12967-020-02390-0.
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.
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.
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). 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).
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.
放射性口腔黏膜炎（OM）是头颈部癌最常见的急性并发症之一。严重的OM与放疗中断相关，这对成功的肿瘤治疗有害。放射基因组学研究表明，基因变异与放疗的不良反应有关。
对1467例鼻咽癌患者进行了大规模全基因组扫描，其中753例接受二维适形放疗（2D-CRT），来自放疗毒性与预后基因结构（GARTP）队列，714例接受调强放疗（IMRT）（192例来自GARTP，522例为新招募）。对顶级关联进行了放疗技术亚组分析。我们还对风险位点进行了物理和调控图谱绘制，并对候选靶基因进行了基因集富集分析。
通过定位图谱、表达定量性状位点（eQTL）图谱、染色质相互作用图谱和基于基因的分析，我们鉴定出50个相关基因组位点和64个基因，其中36个位点在亚组分析中得到重复。有趣的是，位于TNKS（一个与辐射毒性相关的基因）的顶级位点之一，与OM风险增加相关，主效单核苷酸多态性（SNP）rs117157809的比值比（OR）=3.72（95%可信区间2.10-6.57；P=6.33×10）。基因集分析表明，64个候选靶基因在调节端粒封端和维持以及端粒酶活性的生物学过程中富集（顶级P=7.73×10）。
这些结果增强了对放疗毒性的生物学理解。在端粒功能调节中富集的关联信号暗示了潜在的机制，值得进一步进行功能研究和潜在的个体化放疗应用。
