LncRNA在云南宣威地区家族肺癌遗传易感性中的作用机制研究

Xuanwei area in Yunan Province has the highest lung cancer incidence nationwide, in which air pollution is considered as No.1 culprit, especially “smoky coal” combustion. Our previous survey indicated rather than sporadic, lung cancer case in Xuanwei usually happened in family clusters (familial lung cancer). Initially representative lung cancer patients in typical families were selected for whole genome sequencing (WGS) (normal genomic DNA), and transcriptome analysis (RNA-seq) (non-cancerous lung tissue). After bioinformatics processing, a group of LncRNAs emerging as promising candidates for heritable lung cancer susceptibility..Currently air pollution is becoming a burning issue in China. In order to further investigate and verify the significance of selected LncRNAs in family clustering of air pollution-related lung cancer, firstly we plan to bring in low-cancer-rate families from clean areas as controls, systematically compare and analyze the variance spectrum in two family groups on both DNA and RNA level ( WGS and RNA-seq). Secondly, cell experiments is designed to study whether changing LncRNA levels by silencing or overexpression could make normal epithelial cells more vulnerable to air carcinogens, that is affecting their cancer-forming potential. Finally, we would measure target LncRNA levels in lung cancer families, sporadic lung cancer cases and health population, to estimate if they can be used as biomarkers for dignosis and prognosis. .In summary, the project is designed to search and study potential LncRNAs, responsible for or related with heritable lung cancer susceptibility in Xuanwei population; and further investigate the intricate machenism behind the family clustering of lung cancer; how the polluted air help building the unique genetic background of Xuanwei population; and whether this unique genome makeup would further influence or contribute to lung cancer rate in that area. The discoveries would provide essential clue for future research and may eventually helping people with lung cancer family history in susceptibility screen, risk prediction, and diagnostic＆therapeutic strategy development.

云南省宣威地区肺癌发病率高居全国首位，与当地燃煤所致空气污染密切相关。课题组调查发现当地肺癌发病呈明显家族聚集现象，前期对肺癌家组中肺癌患者的全基因组与转录组测序发现：部分LncRNA的变异密度高且转录异常，LncRNA可能是空气污染相关肺癌的重要遗传易感因素，但其作用机制尚不明确。.本研究拟以清洁地区低癌家族为对照，比较两类家系基因组与转录组的系统差异，对目标LncRNA进行分析验证，探索空气污染与LncRNA变异的联系；通过细胞功能实验探讨LncRNA对细胞环境致癌物诱变敏感性的影响，并对其可能的调控机制进行研究；在肺癌家系、散发病例及健康人群中检测LncRNA的表达，评估其作为高危易感人群筛查及肺癌临床诊断和预后指标的价值。研究LncRNA在家族肺癌遗传易感性中的作用，对明确对肺癌家族的遗传易感机制有重要意义，同时也可为高危易感人群筛查、预防、风险评估提供研究线索和理论依据。

云南省宣威地区肺癌高发且家族聚集现象明显，燃煤环境污染是当地主要的致癌因素，宣威肺癌家族是研究“环境-遗传-肺癌”的理想人群。.课题组建立了肺癌家系生物样本库研究发现：宣威地区肺癌家系患者的临床特征独特：发病年龄较早、腺癌、晚期病例比例高，高血压、糖尿病及合并其他癌症情况多见；更易较早发生如息肉、结节及囊肿等病变，双肺多灶性病变（多原发肺癌）比例较高；发病高峰较普通肺癌人群提前10-15年，其中女性发病年龄提前更为明显。家族肺癌史和燃煤暴露对宣威肺癌患者驱动基因EGFR、ALK与 ROS1基因的融合模式具有重要影响，遗传因素显著提高了宣威地区肺癌的发病风险。. 对宣威家族肺癌的基因组测序及生物信分析，筛选出潜在与肺癌遗传易感密切相关的3个lncRNA: LINC00433; LINC00842; LINC00343。通过的血液及组织指标检测及统计分析发现：血细胞LINC00343在男性患者、吸烟肺癌患者群体中高表达，血浆LINC00343在大于55岁肺癌患者、III-IV期肺癌患者中高表达，血细胞LINC00433在肺部多发结节肺癌患者中低表达，血细胞LINC00842在吸烟患者群体中高表达。提示血细胞LINC00343、血浆LINC00343、血细胞LINC00433、血细胞LINC00842可能成为潜在的肺癌诊断、治疗相关的新生物学标志。细胞实验发现：LINC00433和LINC00842在一定条件下表现出抑癌保护功能。LINC00343在一定条件下表现出促癌功能。但是从整体上看：LINC00343和LINC00433的功能比较复杂，呈现多样性。提示非编码RNA家族中的LincRNA在肺癌发生发展过程中复杂多样的调控功能。.本研究明确对肺癌的遗传易感机制有重要意义，同时也可为高危易感人群筛查、预防、风险评估提供研究线索和理论依据，并为肺癌高风险人群的精准筛查、预防和治疗提供参考。. 本项目项目执行期间发表SCI收录论文9篇，其中标注基金资助（No.81702274）SCI论文5篇；完成与该项目相关的硕士学位论文2篇、申请发明型专利2项；受邀在第十一届欧洲地区胸部肿瘤大会上并作题为“云贵高原家族肺癌研究”的大会主题发言，介绍本项目研究成果，本研究部分成果荣获云南省省科技进步特奖励1项。