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 家庭研究表明，环境暴露对肺癌风险有很大贡献 遗传因素的贡献。肺癌联合体(GELCC)的遗传流行病学研究 在过去的20年里，从有很强的LC家族病史的个人那里收集样本和数据，并已 收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家系(高危)的多个亲属上获得的生物样本 家族性肺癌家系、HRFLC病例/家系)以及表型、基因和吸烟数据 至少有一个一级或二级亲属家族史的额外800多例肺癌病例 患有肺癌，但无法从其他亲属那里获得生物样本的患者(家族性病例来自 BIOSPEIMEN LIME家庭，FLC病例)。这项研究应用的目标是识别基因 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 提供对其发展的具体原因和途径的洞察。此外，如果高风险 可以确定个人，他们将从筛查方式中获得最大好处。 我们提出了三个目标。在目标1中，我们将确定与肺部高危相关的遗传因素。 癌症的发展..在这个目标中，我们将完成对33个HRFLC家庭的WES数据的分析 291例肺癌和114例FLC病例及1084例肺癌病例对照分析 相比之下，对照组为919人。我们将使用这些数据和连锁分析来确定不常见的变异的优先顺序 对肺癌风险有很大影响的药物。在目标2中，我们将把调查结果扩展并验证到更广泛的 人口。我们还将从HRLFC的LC病例中收集额外的样本。我们将排出最多的 在其他受影响和未受影响的人中，来自Aim 1的强关联变异和基因 测序的家系和一组额外的FLC病例和频率匹配的对照。这个目标将使我们能够 A)使用更多有肺癌家族史和 控制和b)根据吸烟行为和遗传因素评估对家庭风险的影响。 在目标3中，我们将研究在目标1和2中发现的变异对细胞生物学的影响。我们会 用CRISPR研究特定突变对AIMS 1和2中鉴定的细胞表型的影响 技术我们将首先研究PARK2的突变，我们最近在5个HRLFC家族和 在E2a中，我们以前研究过。这项拟议的研究将为肺癌的病因学带来新的见解。