基于循环DNA检测的新疆维吾尔族、汉族非小细胞肺癌EGFR基因突变及其分子遗传学机制研究

Lung cancer is the leading cause of cancer morbidity and mortality in malignant tumor. Among which, Non-small-cell lung carcinoma (NSCLC) is the main pathological category. The Uygur nationality is group who develop lung cancer with relatively independent genetic background. Ideal therapeutic effect has been observed in NSCLC treated with TKI. Circulating tumor DNA is one of the most important sample resources for detection of EGFR gene mutation. Indicated by our preceding clinical research, detection of EGFR Gene mutation in Han people with NSCLC in Xinjiang applying circulating Tumor DNA detection matches that of Applying tissue. It is unclear whether the same law exists in Uygur people with NSCLC in Xinjiang. Few research reports that EGFR gene mutation rate in NSCLC is different between Uygur patient and Han patient with unclear genetic mechanism. We propose the hypothesis that circulating tumor DNA detection may reflect EGFR Gene mutation in Uygur people with NSCLC in Xinjiang. Further more, the genetic mechanism may be relevant to several key elements in genome. From the view of circulating tumor DNA, this project will evaluate the concordance of circulating tumor DNA detection compared with tissue detection and reveal the EGFR gene mutation pattern and molecular genetic mechanism between the two nations in two aspects as follows: First, from comparative genomics' point of view，copy number variation patterns along with internal mechanism of genetic variation regulation will be investigated. Second, from gene mutation's point of view，the mutation of EGFR will be detected and confirmed with result of comparative genomics each other. From the angle of circulating tumor DNA, this study reveal the character of EGFR gene mutation and molecular genetics mechanism in Uygur patient with NSCLC in Xinjiang.

肺癌居肿瘤发病率和死亡率首位。新疆维吾尔族肺癌的遗传背景相对独立。TKI对EGFR突变阳性的NSCLC疗效确切。循环肿瘤DNA可用于EGFR基因突变检测。我们的前期研究表明，基于循环肿瘤DNA检测NSCLC汉族EGFR突变与组织学相符，尚不明确在维吾尔族是否存在相似规律。基于组织样本的研究表明维吾尔族NSCLC的EGFR突变规律有别于汉族，遗传学机制不清。推测循环DNA检测可能反映维吾尔族肺癌EGFR突变规律，其机制可能与循环DNA基因组突变调控的若干关键元件存在关联。本研究拟以循环肿瘤DNA为切入点，评价其与组织学检测的一致性，探讨EGFR在两个民族间的突变规律及分子遗传机制：一、从比较基因组学角度探讨基因组拷贝数变化模式以及EGFR突变的内在遗传变异调控机制；二、从基因突变角度研究两个民族EGFR基因突变规律，并与基因组差异相互印证，阐释维吾尔族EGFR基因突变差异的分子遗传机制。

本研究着眼于从ctDNA角度揭示新疆维吾尔族非小细胞肺癌基因突变特征及遗传学基础，利用最前沿、高灵敏度与特异性的ctDNA扩增和检测技术，其分析结果对阐释新疆维吾尔族肺癌治疗个体差异的分子遗传机制具有重要基础意义，亦为制定新疆维吾尔族非小细胞肺癌患者最佳个体化给药方案提供遗传药理学依据和临床思路。采用BWA将原始数据比对到HG37参考基因组序列，吉因加自主分析流程进行点突变（SNV）、插入缺失（Indel）、拷贝数变异(CNV)和结构变异（SV）的分析。维吾尔族非小细胞肺癌患者吸烟比例高于汉族非小细胞肺癌患者，腺癌比例低于汉族患者，TMB-H患者中吸烟者比例维吾尔族也显著高于汉族。维吾尔族患者的血浆cfDNA含量高于汉族患者人群，但基因突变率更低，ABCC11基因突变在维吾尔族非小细胞肺癌人群中更为普遍。相比汉族非小细胞肺癌人群，维吾尔族非小细胞肺癌人群具有更显著的Wnt通路富集，以及以磷酸肌醇磷酸酶活性为代表的5类功能突变。