A Functional 5′-UTR Polymorphism of MYC Contributes to Nasopharyngeal Carcinoma Susceptibility and Chemoradiotherapy Induced Toxicities
A Functional 5′-UTR Polymorphism of MYC Contributes to Nasopharyngeal Carcinoma Susceptibility and Chemoradiotherapy Induced Toxicities
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DOI：
10.7150/jca.28534
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Guo, Zhen;Wang, Youhong;Zhang, Wei
MYC是一种转录因子，作为参与细胞周期进程、凋亡、分化和代谢的基因的关键调节因子。本研究旨在探讨MYC基因多态性与中国人群鼻咽癌风险及放化疗毒副反应的关系。采用生物信息学方法对684例鼻咽癌患者和823例健康对照者进行MYC基因5个潜在功能性单核苷酸多态性的基因分型。发现两个SNPs rs 4645948（C>T）和rs 2071346（G>T）与鼻咽癌的发生风险显著相关（TT+CT vs CC，OR=1.557，P=3.34x10（-4）; TT+GT vs GG，OR=1.361，P=0.007）。此外，rs 4645948（C>T）与接受放化疗的鼻咽癌患者贫血（CT vs CC，OR=2.152，P=0.001）和严重白细胞减少（CT vs CC，OR=1.893，P=0.034）的风险增加有关。rs 2071346（G>T）变异基因型携带者贫血（GT vs GG，OR=1.665，P=0.022）和血小板减少（GT vs GG，OR=1.685，P=0.035）的危险性更高。我们的研究结果表明，MYC的相对表达量显着高于鼻咽癌组织相比，鼻炎组织。MYC的过度表达与T分期、N分期及临床分期的晚期呈正相关。值得注意的是，MYC在rs 4645948 CT和TT基因型携带者中的表达显著高于CC基因型携带者。荧光素酶报告基因分析表明，rs 4645948的T等位基因导致MYC的转录活性显著高于C等位基因。这些发现表明，携带rs 4645948 T等位基因的个体可能由于MYC转录活性的增加和MYC表达的增加而具有更高的NPC风险。
MYC is a transcription factor acting as a pivotal regulator of genes involved in cell cycle progression, apoptosis, differentiation and metabolism. In this study, we evaluated the association of MYC polymorphisms with nasopharyngeal carcinoma (NPC) risk and chemoradiotherapy induced toxicities among Chinese population. By using bioinformatic tools, five potential functional single nucleotide polymorphisms of MYC were genotyped in a case-control study with 684 NPC patients and 823 healthy controls. We found two SNPs rs4645948 (C>T) and rs2071346 (G>T) were significantly associated with increased risk of developing NPC (TT+CT vs CC, OR=1.557, P=3.34x10(-4); TT+GT vs GG, OR=1.361, P=0.007, respectively). In addition, rs4645948 (C>T) was conferred with increased risk of anemia (CT vs CC, OR=2.152, P=0.001) and severe leukopenia (CT vs CC, OR=1.893, P=0.034) for NPC patients receiving chemoradiotherapy. We also found rs2071346 (G>T) variant genotype carriers were subjected to higher risk of anemia (GT vs GG, OR=1.665, P=0.022) and thrombocytopenia (GT vs GG, OR=1.685, P=0.035). Our results demonstrated that the relative expression of MYC was dramatically higher in NPC tissues compared to rhinitis tissues. Over-expression of MYC was positively correlated with advanced T stage, N stage, and late clinical stage. Notably, the expression of MYC in rs4645948 CT and TT genotypes carriers were significantly higher than CC genotype carriers. Luciferase reporter assay indicated that the T allele of rs4645948 led to significantly higher transcription activity of MYC compared to the C allele. These findings suggested that individual carrying the rs4645948 T allele may be at greater risk for NPC due to an increase of MYC transcriptional activity and an augment of MYC expression.