鼻咽癌是起源于鼻咽上皮的一种特殊类型的头颈癌。鼻咽癌具有显著的地域和人种特征，主要在我国华南和东南亚国家高发。鼻咽癌的确切病因尚未完全阐明，相应的自发性鼻咽癌动物模型也一直没有建立起来。鼻咽癌的发生一般被认为是多因素联合作用的结果，包括遗传易感、EB病毒感染和环境因素。EB病毒曾被认为是鼻咽癌的致病因子，然而EB病毒癌基因的转基因小鼠并不能模拟鼻咽癌的发生。除了EB病毒感染，家族聚集性是鼻咽癌的一大特征，提示遗传易感性可能是鼻咽癌的首要病因。申请人利用团队前期的全基因组关联分析（GWAS）结果，重点解析了一个在鼻咽癌中获得性高表达的易感基因TNFRSF19的体内功能，阐明了其分子机制。前期数据显示，尽管鼻咽癌和它的近亲头颈癌拥有不同的基因异常，但在导致的信号通路紊乱上具有很大的相似之处。申请人将建立鼻咽癌易感基因TNFRSF19的转基因小鼠模型，验证遗传易感性和这一罕见肿瘤的因果关系。

Nasopharyngeal carcinoma (NPC) is a unique type of head and neck cancer that arises from the epithelium of the nasopharynx. NPC exhibits a striking geographic and ethnic distribution, the incidence of NPC is unusually high in Southeast Asia and southern China, but rare worldwide. The exact genetic changes attributable for the pathogenesis of NPC are still elusive, as a result the genetically engineered mouse models (GEMM) that mimicking spontaneous NPC are currently unavailable. Multiple factors, including genetic susceptibility, Epstein-Barr virus (EBV) infection and environmental factors contribute to NPC development. EBV has been proposed as a driving factor in NPC pathogenesis, however, transgenic mouse models carrying EBV oncogenes do not develop tumors, indicating that viral infection may not contribute to NPC initiation. Besides the presence of EBV, familiar aggregation of NPC and the occurrence of multiple cases of the disease in first-degree relatives have been reported in endemic regions, strongly indicating that genetic susceptibility is a major determinant of NPC. Based on the discoveries from our previous NPC genome-wide association study (GWAS), we focused on a NPC susceptibility gene TNFRSF19, which is highly expressed in NPC and is required for cell proliferation and NPC development. By studying TNFRSF19, we gained insights into the functional mechanisms responsible for increased susceptibility to NPC. The preliminary results indicate that despite the distinct aberrant genes between NPC and head and neck cancer, they share common aberrant signaling pathway that driving tumorigenesis. The applicant aims to generate Tnfrsf19 transgenic mouse model to prove the causal role of genetic susceptibility in NPC pathogenesis.