Sequencing Familial Lung Cancer

家族性肺癌测序

• 批准号: 10548750
• 负责人: Christopher I. Amos
• 金额: $ 64.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-22 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548750
• 关键词: Affect; Biological; CRISPR/Cas technology; Cancer Etiology; Cancer Family; Cell Line; Cellular biology; Collection; DNA Library; Data; Development; Environmental Exposure; Epidermal Growth Factor Receptor; Etiology; Family; Family Cancer History; Family Study; Family history of; Family member; Frequencies; Generations; Genes; Genetic; Genotype; Goals; Grant; Individual; Inherited; Joints; Malignant Neoplasms; Malignant neoplasm of lung; Modality; Mutation; PARK2 gene; Participant; Pathway interactions; Penetrance; Phenotype; Population; Predisposition; Prevention; Prevention Measures; RB1 gene; Recording of previous events; Research; Resources; Risk; Risk Factors; Role; Sampling; Sampling Studies; Second Degree Relative; Smoking; Smoking Behavior; Smoking History; Specimen; TCF3 gene; TP53 gene; Testing; Tobacco smoking behavior; Toxic Environmental Substances; Update; Variant; cancer risk; data resource; exome sequencing; genetic analysis; genetic epidemiology; genetic linkage analysis; genetic selection; genetic variant; genome wide association study; high risk; high risk population; indexing; insight; member; mortality; next generation; novel; proband; risk variant; screening; smoking exposure; targeted sequencing; tobacco smoke exposure; tumorigenesis

Lung cancer (LC) is the leading cause of cancer mortality in the U.S. Although tobacco smoking and some environmental exposures contribute substantially to lung cancer risk, family studies show an additional strong contribution from genetic factors. The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has been collecting samples and data from individuals with a strong family history of LC for the last 20 years, and has assembled a unique resource of specimens and data. We have cancer phenotypes, smoking exposure data and biological specimens available on multiple relatives in over 150 highly aggregated LC families (high-risk familial lung cancer families, HRFLC cases/families) as well as phenotype, genotype and smoking data on over 800 additional lung cancer cases who have a family history of at least one first or second degree relative with lung cancer but for whom biospecimens were not available from additional relatives (familial cases from biospecimen limited families, FLC cases). The goal of this research application is to identify genetic factors that confer a high risk for lung cancer and to perform research to characterize further the mechanisms by which these factors influence lung cancer risk. Identifying genetic factors for lung cancer provides insight into the specific causes and pathways underlying its development. In addition, if high-risk individuals can be identified they will reap the greatest benefit from screening modalities. We propose three aims. In aim 1 we will identify genetic factors conferring a high-risk of lung cancer development.. In this aim, we will complete analyses of WES data from 33 HRFLC families comprising 291 individuals along with 114 FLC cases and case/control analyses of 1084 lung cancer cases compared with 919 controls. We will use these data along with linkage analysis to prioritize uncommon variants that have a strong effect on lung cancer risk. In Aim 2 we will extend and validate findings to a broader population. We will also collect additional samples from LC cases in HRLFC. We will sequence the most strongly associated variants and genes from Aim 1 in additional affected and unaffected individuals in the sequenced families and an additional set of FLC cases and frequency matched controls. This aim will allow us to a) validate findings from aim 1 using a larger collection of cases with a family history of lung cancer and controls and b) assess the impact on risk in families according to smoking behavior and genetic contributions. In Aim 3 we will study the impact that variants found in aims 1 and 2 have on cellular biology. We will study the effect that specific mutations have on cellular phenotypes identified in aims 1 and 2 using CRISPR technology. We will begin by studying mutations in PARK2 that we recently identified in 5 HRLFC families and in E2A we previously studied. The proposed research will bring new insights into the etiology of lung cancer.

肺癌 (LC) 是美国癌症死亡的主要原因。尽管吸烟和一些癌症 家庭研究表明，环境暴露对肺癌风险有很大影响 遗传因素的贡献。肺癌遗传流行病学联盟 (GELCC) 从过去 20 年有明显 LC 家族史的个体中收集样本和数据，并已 汇集了独特的样本和数据资源。我们有癌症表型、吸烟暴露数据 以及 150 多个高度聚集的 LC 家族（高风险 家族性肺癌家族、HRFLC 病例/家族）以及表型、基因型和吸烟数据 超过 800 例肺癌病例至少有一名一级或二级亲属有家族史 患有肺癌，但无法从其他亲属处获得生物样本（家族病例来自 生物样本有限家庭，FLC 病例）。本研究应用的目标是识别遗传 导致肺癌高风险的因素，并进行研究以进一步表征 这些因素影响肺癌风险的机制。识别肺癌的遗传因素 深入了解其发展的具体原因和途径。另外，如果存在高风险 可以确定哪些人将从筛查方式中获得最大利益。 我们提出三个目标。在目标 1 中，我们将确定导致肺癌高风险的遗传因素 癌症发展..为了这个目标，我们将完成对 33 个 HRFLC 家族的 WES 数据的分析 包括 291 人以及 114 例 FLC 病例和 1084 例肺癌病例的病例/对照分析 与 919 对照相比。我们将使用这些数据以及连锁分析来优先考虑不常见的变异 对肺癌风险有很大影响。在目标 2 中，我们将把研究结果扩展到更广泛的领域并进行验证 人口。我们还将从 HRLFC 的 LC 案例中收集更多样本。我们将排序最多 在其他受影响和未受影响的个体中，与目标 1 密切相关的变异和基因 测序的家庭和一组额外的 FLC 病例和频率匹配对照。这个目标将使我们 a) 使用更多具有肺癌家族史的病例来验证目标 1 的结果，并且 b) 根据吸烟行为和遗传贡献评估对家庭风险的影响。 在目标 3 中，我们将研究目标 1 和 2 中发现的变异对细胞生物学的影响。我们将 使用 CRISPR 研究特定突变对目标 1 和 2 中确定的细胞表型的影响 技术。我们将首先研究最近在 5 个 HRLFC 家族中发现的 PARK2 突变， 在我们之前研究过的E2A中。拟议的研究将为肺癌的病因学带来新的见解。