DNA双链断裂修复相关基因单核苷酸变异与头颈鳞癌发生风险的相关性研究

Tobacco smoke, alcohol drinking and germline variants are the major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Smoking and drinking cause DNA damage leading to apoptosis, suboptimal of DNA repair capacity and insufficient apoptotic capacity may favor development of cancer because of the dysfunction of removing damaged cells. Tobacco carcinogens cause many types of DNA damage in the target epithelial cells; DNA double-strand break (DSB) is one of the most serious forms of DNA damage to the cells. In the grant application, we hypothesize that suboptimal DNA DSB repair capacity is associated with an increased risk of SCCHN and the association is modified by functional genetic variants. We will test our hypothesis by measuring DSB repair capacity using flow cytometry-based assays with peripheral blood lymphocytes (PBLs) derived from 600 cases and 600 frequency-matched hospital-based controls with/without etoposide-induced DSB repair phenotype. The targeted next-generation sequencing (i.e., RAD51, BRCA1, to sequence 45 key DSB pathway genes, including the promoter and exon for each gene) will also be applied to DNA samples from PBLs in the hospital-based case-control study. We will comprehensive evaluate the relationships of gene-gene, genotype-phenotype and joint-effect of gene-environment, phenotype-environment in the etiology of SCCHN. The goal of our research is to identify effective biomarker for risk assessment of SCCHN and to identify at-risk individuals who can be targeted for primary prevention and treatment of SCCHN in the Chinese general population.

吸烟、饮酒和遗传变异是头颈部鳞癌发生的主要因素，而环境致癌物可引起 DNA损伤而诱导细胞凋亡，双链断裂是各种DNA损伤中最严重的类型，其修复能力至关重要。我们的前期研究显示，在北美白人中，细胞DNA双链断裂的修复能力和细胞凋亡能力的降低与头颈鳞癌的风险增加密切相关；双链断裂修复基因RAD51罕见变异携带者比野生型携带者患头颈鳞癌的风险高达3.60倍。因此我们推测“DNA 双链断裂的修复能力与头颈部鳞癌发生风险密切相关，其修复能力的改变可能由单核苷酸变异引起”。本课题拟采用体外细胞培养和流式细胞检测技术测定中国600例头颈鳞癌患者和600例正常人外周血淋巴细胞DNA双链断裂修复能力，并对包括RAD51的45个双链断裂修复的候选基因行新一代DNA靶向测序，通过生物信息分析来验证我们的假说。找出有效的生物标志物为头颈部鳞癌的个体化预防和靶向治疗及药物疗效预测提供重要参考。

在致癌物作用下，正常人体细胞可出现多种DNA损伤，而DNA损伤得不到及时修复或细胞自噬和凋亡障碍，最终可导致癌症的发生。本研究以中国汉族人群样本为研究群体，研究DNA双链断裂修复基因的基因型与表型的相互关系及其他因素交互效应在头颈鳞癌、甲状腺癌、肺癌发病中的作用，并找出与肿瘤风险相关的有效生物标志物。我们的研究发现：在我国汉族人群中，DNA双链断裂修复能力降低与头颈鳞癌、甲状腺癌、肺癌发生风险均相关，DNA双链断裂修复能力降低，个体肿瘤发病风险增高。同时新一代靶向DNA测序结果显示AGAP1基因变异与头颈鳞癌发生风险相关；RAD50和FANCA基因变异与甲状腺癌发病风险相关；BRIP1、RAD52基因变异与肺癌发生风险相关。在此基础上，我们对肺癌群体进行亚组分析，分析结果显示DNA双链断裂高修复能力组，其肺癌的死亡和复发风险增加。我们的研究在丰富肿瘤病因学的同时，为后续针对DNA双链断裂修复在肿瘤发病中的深入研究奠定了基础，为临床诊断及治疗提供了更有前景的肿瘤生物标志物和治疗靶标。

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