家族聚集性肺癌遗传易患性的分子遗传学机制研究

Lung cancer raised upon the interaction between genetic and environment factors.Familial aggressive lung cancer patients share a same genetic background so that provide a chance to find environment response genes and their relative risk in carcinogenesis when aberration occurs. In this study, we will take advantage ofthe newly developed next generation sequencing technology and apply whole genomeexome sequencing to the samples collected from a cohort of familial aggressive lung cancer patients. After exome capture and deep sequencing, a set of bioinformatics analysis will be employed to find DNA aberrations in each genome, including mutation and INDELs. The aberrations will be further validated by mass spectrum or standard Sanger sequencing method to get aberration profile with high confidence for each individual. We further employ statistic analysis on these genome aberration profile in couple with the individual's environment exposure to find those environment response gene/loci and their aberration, which will be further investigate in a separate lung cancer cohort. As we known, this proposed study is the first one to apply whole genome sequencing analysis to familial aggressive lung cancer. Findings from this study may shed light on the mechanism of genetics-environment interaction in carcinogenesis and also give hints for genes/loci with potential value for clinical diagnosis and therapy.

肺癌的发生是环境与遗传因素相互作用，多基因共同参与的复杂病理过程。本项研究将以新一代测序技术为基本方法，通过对一组家族聚集性肺腺癌患者的肿瘤患者及其亲属的外周血有核细胞基因组DNA 样品的全外显子组序列分析，结合Sequenom 飞行质谱等方法的验证，在生物信息学分析的基础上，获得研究对象的胚系突变谱（基于血细胞）。从中发现与这类肺腺癌发生高度相关的"遗传易患基因"；将个体所处环境因素与其积累的DNA 突变谱进行关联研究，获得与癌变发生密切相关的关键"环境应答基因"及其序列变异。从基因组层面揭示在肺癌发生过程中环境与遗传因素相互作用的分子机制；为筛选肺癌候选诊断标志物及治疗靶点提供新的线索。

本项目收集了一个三代12 人之中5 人（一代5 兄妹之中4 人）罹患肺腺癌的家族聚集性肺癌家系。将肿瘤组织基因组DNA 样品、患者及其亲属的外周血有核细胞提取基因组DNA后，进行DNA样品经质控，质控合格后制备了全部DNA样本测序文库，经全外显子测序分析，最终获得了10例样品的高质量外显子测序数据（包括3例肿瘤组织及7例外周血样品）。经过比对分析和校正，获得每个样品中存在的胚系突变（SNP/Indel）位点信息肿瘤组织中发生的体细胞突变。由于仅获得了1年期的10万元项目资助，经费和时间的限制尚不及作进一步的数据挖掘与实验验证。