Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy.
Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy.
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鼻咽癌放疗患者急性口腔粘膜炎的预测单核苷酸多态性标记物
DOI：
10.18632/oncotarget.18450
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发表时间：
2017-09-08
期刊：
影响因子：
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通讯作者：
Liu Y
中科院分区：
文献类型：
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作者：
Le Z;Niu X;Chen Y;Ou X;Zhao G;Liu Q;Tu W;Hu C;Kong L;Liu Y
本研究旨在探讨中国人鼻咽癌(NPC)放疗患者严重口腔黏膜炎(OM)的易感性与全基因组单核苷酸多态(SNPs)的关系。对24例鼻咽癌患者进行SNPs筛查，对6例鼻咽癌患者进行基因表达分析。根据CTC评分将患者分为CTC 0~2级(CTC毒性0、1、2级)和CTC3+组(CTC毒性3级及以上)。使用GTEx数据集进行eQTL分析，并对eQTL相关基因进行体外功能分析。我们的数据确定了7个与OM发生相关的功能SNPs。我们观察到，位于ZNF24基因5‘端非编码区的rs11081899-A与重度粘膜炎的危险性显著相关(OR=14.631，95%CI=2.61-105.46，p=1.2×10−4)，并与GTEx数据集ZNF24基因的表达呈正相关(p=4.1×10−6)。此外，ZNF24mRNA的高表达与鼻咽癌患者的严重OM相关(p=0.02)。进一步的功能分析显示，ZNF24基因敲除可降低p65的表达，并抑制肿瘤坏死因子-α诱导的NF-κB活化和促炎细胞因子的释放。这些发现提示rs11081899-A可能是鼻咽癌患者放射性OM的一个遗传易感因素，但其临床应用价值仍需在大样本队列中进一步验证。此外，我们认为ZNF24的下调可能通过抑制NF-κB的激活而延缓粘膜炎的发展。
The aim of this study was to investigate the association between the susceptibility of severe oral mucositis (OM) in Chinese nasopharyngeal carcinoma (NPC) patients treated with radiotherapy and single nucleotide polymorphisms (SNPs) across the whole genome. SNPs were screened in a total of 24 patients with NPC and an additional 6 were subjected to mRNA expression analysis. Patients were subdivided into CTC 0-2 (CTC toxicity grade 0, 1, and 2) and CTC 3+ (CTC toxicity grade 3 and above) groups according to their CTC (common toxicity criteria) scores. The GTEx dataset was used to performed eQTL analyses and in-vitro functional assays were performed for eQTL-associated genes. Our data identified 7 functional SNPs associated with the development of OM. We observed that rs11081899-A, located in the 5′-UTR of the ZNF24 gene, was significantly correlated with a higher risk of severe mucositis (OR = 14.631, 95% CI = 2.61-105.46, p = 1.2 × 10−4), and positively associated with ZNF24 mRNA expression (p = 4.1 × 10−6) from GTEx dataset. In addition, high ZNF24 mRNA expression was associated with severe OM in patients with NPC (p = 0.02). Further functional assays revealed that ZNF24 knockdown reduced p65 expression and suppressed TNF-α-induced NF-κB activation and pro-inflammatory cytokines release. These findings suggested that rs11081899-A may be a genetic susceptibility factor for radiation-induced OM in patients with NPC, although its value in clinical application needs to be further verified in a large cohort. Also, we suggested that downregulation of ZNF24 may attenuate the development of mucositis by suppressing NF-κB activation.