鼻咽癌糖酵解通路关键基因遗传多态对放射敏感性的影响

Warburg effect is an important feature of tumors,and genetic variation is one of the main factors of individual differences to radiotherapy treatment response for nasopharyngeal carcinoma(NPC). Through the previous work we found that the p53 codon72 (Pro/Arg) was related to the prognosis of NPC; Using the method of proteomics, we discovered glycolysis related gene such as PGK1, ALDOA， was associated with radiosensitivity.Thus,with all the previous work we have done,we hypothesize that the key gene polymorphisms in glycolytic pathway, such as p53 , influence the glycolytic pathway,which leads to differences in radiosensitivity of NPC. Our projects will include 600 cases of patients with NPC to detect common glycolytic key genes polymorphisms. Besides,we correlate these factors with their radiosensitivity and prognosis.Then, prediction model will be established, and validation of the prediction model will be done. Using enzyme-labeling instrument ，comet assay and clonogenic assay，cytological experiments will further investigate the influence of key gene polymorphisms on the glycolysis efficiency and mechanism of radiation sensitivity.Thus,we could provide theoretical basis of individualized treatment for NPC.

Warburg效应是肿瘤的重要特征之一，遗传变异是鼻咽癌放疗反应个体差异的主要因素之一。前期工作中我们发现p53 codon72(Pro/Arg)与鼻咽癌预后相关；利用蛋白质组学方法发现糖酵解相关基因PGK1、ALDOA与鼻咽癌放射敏感性相关。我们推测p53等糖酵解途径关键基因多态通过影响糖酵解通路，从而导致鼻咽癌放射敏感性差异。项目将首先纳入600例鼻咽癌患者，通过检测血标本糖酵解关键基因常见多态，证实基因多态是否能影响鼻咽癌放疗反应。进而建立SNP预测放射敏感性模型，并验证。细胞学实验采用酶标仪法测酶活性、彗星实验、集落形成实验等，进一步研究关键基因多态性对糖酵解效率及放射敏感性的影响及机制，为个体化治疗提供理论依据。

遗传变异被认为是导致鼻咽癌放疗个体差异的主要因素之一。以Warburg效应为主的通路是肿瘤的重要特征之一。既往研究发现，单核苷酸多态性可通过影响肿瘤通路，导致鼻咽癌放化疗敏感性差异。本次研究旨在发现糖酵解相关通路中预测鼻咽癌易感性、治疗敏感性等的基因位点。易感性方面，相关位点HK2 rs2229629、rs656489、HIF-1α rs17099567、rs10136168等携带人群患者风险差异明显。在急性毒性方面，相关位点HIF1-α rs17099567、rs8006839与皮肤炎相关，MEG3 rs10132552和LINC-ROR rs2027701、GAS5 rs2067079、rs6790与骨髓抑制相关。在疗效方面，GCK rs2268573被证实可预测鼻咽癌近期疗效。因此，本研究已发现糖酵解等多种代谢、修复通路单核苷酸多态性可预测、影响肿瘤进程，为今后鼻咽癌个体化治疗奠定基础。