Sequencing Familial Lung Cancer

家族性肺癌测序

• 批准号: 9916400
• 负责人: Christopher I. Amos
• 金额: $ 73.51万
• 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/9916400
• 关键词: Affect; Behavioral Genetics; Biological; CRISPR/Cas technology; Cancer Control; 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; Genetic study; Genotype; Goals; Grant; Individual; Inherited; Joints; Malignant Neoplasms; Malignant neoplasm of lung; Modality; Mutation; PARK2 gene; Participant; Pathway interactions; Penetrance; Phenotype; Play; 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 smoke; Tobacco smoking behavior; Toxic Environmental Substances; Update; Variant; cancer risk; case control; data resource; exome sequencing; genetic analysis; genetic epidemiology; genetic linkage analysis; genetic variant; genome wide association study; high risk; indexing; insight; member; mortality; next generation; novel; proband; risk variant; screening; targeted sequencing; 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）是美国癌症死亡率的主要原因。 环境暴露对肺癌风险有很大贡献，家庭研究显示， 遗传因素的贡献。肺癌遗传流行病学联盟（GELCC） 在过去的20年里，从有很强的LC家族史的个体中收集样本和数据， 汇集了独一无二的标本和数据资源我们有癌症表型，吸烟暴露数据 在150多个高度聚集的LC家族（高风险）中的多个亲属中可获得生物标本 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例额外的肺癌病例，他们至少有一个一级或二级亲属的家族史 患有肺癌，但无法从其他亲属获得生物标本的患者（ 生物样本有限家族，FLC病例）。这项研究应用的目标是确定遗传 肺癌的高风险因素，并进行研究，以进一步表征 这些因素影响肺癌风险的机制。肺癌的遗传因素 提供了深入了解其发展的具体原因和途径。此外，如果高风险 个人可以被识别，他们将从筛查模式中获得最大的好处。 我们提出三个目标。在目标1中，我们将确定遗传因素赋予高风险的肺 癌症发展为此，我们将对33个HRFLC家系的WES资料进行分析 包括沿着291例患者和114例FLC病例以及1084例肺癌病例的病例/对照分析 对照组919例。我们将使用这些数据沿着连锁分析，以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，我们将扩展和验证发现，以更广泛的 人口我们还将从HRLFC的LC病例中收集更多样本。我们将测序 在其他受影响和未受影响的个体中， 测序的家庭和一组额外的FLC病例和频率匹配的对照。这一目标将使我们 a）使用大量有肺癌家族史的病例，验证目标1的结果， 控制和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和目标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中鉴定的细胞表型的影响 技术.我们将开始研究PARK 2的突变，我们最近在5个HRLFC家族中发现了突变， 在我们之前研究的E2 A中。这项研究将为肺癌的病因学带来新的见解。