槟榔相关口腔癌致病基因的鉴定及其机制研究

Oral cancer is one of the most serious threats to the health of Chinese population. Previous study have shown that oral cancer can be attributed to smoking and alcohol exposure in developed countries; however, chewing areca is also proved to be the main factor for the development of oral cancer in some regions including China and its specific pathogenesis is not clear. Our research group have used whole-exome sequencing to study 40 primary oral cancer tumors (areca and smoking exposure) and compared the mutations to that of oral cancers based on TCGA sequencing data (all smokers without areca chewing history). The preliminary analysis has indicated that mutation spectrums related to areca and smoking exposures may have a high degree of heterogeneity for oral squamous cell carcinoma. Therefore, based on the latest research progress and previous research results, we will further expand the samples to give a comprehensive depiction of oral squamous cell carcinoma mutation patterns related to areca (with smoking) and smoking, respectively, and compare the similarities and differences between the two mutation spectrums. We hope to identify areca-specific genes not previously implicated in this malignancy and investigate the corresponding biological mechanism of causal mutations and genes. The findings will deeply reveal the biological mechanism in oral cancer development and provide new targets for the individualized precision therapy of oral cancer.

口腔癌是严重威胁我国居民健康的恶性肿瘤之一。既往研究表明欧美等发达国家75%以上的口腔癌可归咎于吸烟和饮酒暴露，然而嚼食槟榔也被证明是包括我国在内部分地区口腔癌高发的主要因素，但其特异的致病基因及生物学机制并不明确。本课题组先期通过全外显子组测序技术，对40例口腔鳞癌（槟榔合并吸烟）癌组织及其配对血液样本进行了全外显子组测序，并结合TCGA口腔鳞癌测序数据（无槟榔嚼食史的吸烟者）初步比较分析发现，槟榔和吸烟等不同环境暴露所致的口腔鳞癌突变谱可能具有高度异质性。因此，本研究拟综合最新研究进展和课题组先期研究结果，扩大样本全面描绘槟榔（合并吸烟）和吸烟相关口腔鳞癌的基因组突变图谱，并比较两者突变特征的异同，进而鉴定槟榔特异的致病基因，同时结合功能学实验探讨相应的生物学机制。研究结果不仅有助于深入阐明口腔鳞癌发生的具体生物学机制，还可进一步筛选和鉴定治疗靶点，为口腔鳞癌的个体化精准医疗提供依据。

咀嚼槟榔是包括我国在内部分地区口腔鳞癌高发的主要危险因素之一，但其特异的致病基因及生物学机制尚不明确。本课题基于89例槟榔相关口腔鳞癌患者、340例非槟榔相关口腔鳞癌患者、50例外部独立口腔鳞癌患者的全外显子组测序数据，绘制了槟榔相关口腔鳞癌的体细胞突变全景图，在验证既往文献报道的7个口腔鳞癌驱动基因的基础之上，新鉴定出两个槟榔相关口腔鳞癌特异的驱动基因WEE1和ATG2A，并在独立人群中得到了验证。体内外功能学实验进一步阐明了WEE1和ATG2A对口腔鳞癌发生发展具有促进作用。此外，还通过比较槟榔相关及非槟榔相关口腔鳞癌患者的突变模式，发现在槟榔相关口腔鳞癌患者中错配修复缺陷突变信号（dMMR）丰度显著升高，该信号丰度升高与患者较差的临床预后相关，可能是促进槟榔相关口腔鳞癌发生的主要机制之一，同时，槟榔相关及dMMR信号丰度较高的患者中，免疫抑制分子PD-L1表达水平显著升高，提示该类患者可能从PD-1/PD-L1免疫疗法中获益。本研究首次在中国人群中鉴定出槟榔暴露特异相关驱动基因与突变信号，为深入研究槟榔相关口腔鳞癌发生机制及其体细胞突变基因功能提供了基础，还可进一步筛选和鉴定治疗靶点，为槟榔相关口腔鳞癌的个体化精准诊疗提供依据。