鼻咽癌易感基因交互作用及致病机理研究

Nasopharyngeal carcinoma (NPC) is a malignant tumor prevalent in Southern China. Although the genetic susceptibility has implicated in the etiology of NPC, the underlying mechanism is still unclear. NPC is a multifactorial complex disease whose pathogenic mechanism involves involves complicated pathogenic networks composed of multiple genetic risk factors and their complex interplays. Our previous study successfully identified important gene-gene interactions involved in complex diseases, and validated their molecular mechanisms involved in the etiology of complex disease. Our results indicated that systematical study of the involved mechanisms of gene-gene interactions underlying NPC can provide new insights towards the better understanding of the genetic susceptibility associated with NPC. However, large scale genome-wide gene-gene interaction studies have not yet been carried out, especially for populations of high prevalent southern china. Based on our previous genome-wide association study on NPC, this study is intended to detect genome-wide gene-gene interactions underlying NPC and illustrate the network basis of the complicated multi-gene pathogenic networks involved in NPC etiology. next, this study aims to characterize the molecular basis of gene-gene interactions involved in the development, invasion and metastasis of tumor cells of NPC, in order to reveal the molecular mechanisms underlying the contribution of gene-gene interplays to the development of NPC. Furthermore, this study is intended to reversely reconstruct the gene network associated with NPC risk and to identify the susceptible functional module and key hub genes. The findings of this study are anticipated to provide important targets and evidence for early diagnosis and risk prediction of NPC.

鼻咽癌是我国华南地区高发的恶性肿瘤。遗传易感性与鼻咽癌发生密切相关，但其致病机制仍有待研究。鼻咽癌致病易感性的重要来源是多个遗传因子间相互作用构成的复杂病因网络。课题组前期研究成功定位复杂疾病重要的基因交互作用，并通过功能实验明确其致病分子机制，提示系统研究基因相互作用在鼻咽癌发生发展中的致病机理，可为揭示鼻咽癌多基因致病机理带来新的策略和视角。但是，目前大规模的鼻咽癌易感基因交互作用研究十分匮乏。因此，本课题拟在前期鼻咽癌全基因组关联研究的基础上，结合生物信息学与分子生物学研究策略，在全基因组范围定位对鼻咽癌发生发展有重要影响的易感基因交互作用，阐明鼻咽癌的多基因复杂病因网络基础；明确基因交互作用对肿瘤生长、侵袭和转移的致癌分子基础，揭示其参与鼻咽癌发生发展过程的分子机制；进一步逆向重构鼻咽癌风险基因网络，挖掘肿瘤发生相关的核心功能模块及关键基因，为鼻咽癌早期诊断和预警提供重要理论依据。

鼻咽癌是好发于我国华南地区的恶性肿瘤，其致病机制与遗传易感性密切相关。基因间复杂的交互作用是鼻咽癌致病易感性的一个重要来源，是鼻咽癌“遗传度缺失”现象的一个重要原因，但目前尚缺乏对鼻咽癌全基因组基因交互作用研究的大规模系统性评估。我们在前期鼻咽癌全基因组关联研究的基础上，在全基因组范围内定位对鼻咽癌致病相关的易感基因交互作用，逆向重构鼻咽癌风险基因网络，挖掘肿瘤发生相关的关键核心基因，为鼻咽癌早期诊断和预警提供重要理论依据。我们完成了鼻咽癌全基因组SNP交互作用的筛查，检测到P＜10e-6的SNP互作对约4万对，其中最显著的对子是C6orf89与RPTOR（P=4.66e-11），并发现多数具有强交互信号的SNP对子仅显现微弱的边际效应，在单位点关联分析时易被遗漏。逆向构建基因交互作用网络发现其具备“小世界”拓扑性质，其中CSMD1和FXN等基因在互作网络中处于重要拓扑位置，可能是鼻咽癌多基因病因网络中的潜在关键基因。此外，我们探讨了鼻咽癌“缺失遗传度”的另外两个重要原因：X染色体易感性和拷贝数变异。我们发现X染色体基因DMD和ARHGAP6等是潜在的鼻咽癌易感基因，且X染色体对鼻咽癌的遗传易感贡献有显著的性别差异，并通过而基因-性别交互作用分析定位了鼻咽癌男性好发现象的潜在关联位点。我们还识别了DACH1基因拷贝数缺失可能是候选的鼻咽癌易感变异事件，CCR3和IL8-CXCR2等DNA损伤修复通路具有较高的拷贝数变异负荷。最后，我们探索性地以系统性红斑狼疮作为复杂疾病模型，开展了宿主易感基因与肠道菌群之间的交互作用研究，探讨易感基因-肠道菌群交互作用与复杂疾病易感性之间的关系。我们发现携带ARID5B易感SNP风险等位基因可促进狼疮患者风险菌群Escherichia属丰度的上调及肠道微生态紊乱，表明肠道菌群与宿主遗传易感性间的交互作用对复杂疾病易感性的贡献不容忽视。