Genome-Wide Association Studies of Inherited Predisposition to Lung Cancer

肺癌遗传易感性的全基因组关联研究

• 批准号: 8471070
• 负责人: Pengyuan Liu
• 金额: $ 41.58万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471070
• 关键词: Air; Alleles; Cancer Etiology; Cancer Family; Candidate Disease Gene; Cessation of life; Code; Comparative Study; Complex; Data; Development; Disease Progression; Effectiveness; Environmental Risk Factor; Functional RNA; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genomics; Goals; Health; Homologous Gene; Human; Human Genome; Human Identifications; Inbred Mouse; Inbred Strains Mice; Individual; Lead; Linkage Disequilibrium; Lung; Lung Adenoma; Lung Neoplasms; Malignant neoplasm of lung; Maps; Methods; Mouse Strains; Mus; Oncogenes; Partner in relationship; Penetrance; Phenotype; Population; Predisposition; Quantitative Trait Loci; Recommendation; Recovery; Resistance; Resources; Risk; Single Nucleotide Polymorphism; Smoking; Structure; Study models; Susceptibility Gene; Time; Tobacco; Tobacco smoke; United States; Woman; base; cancer genetics; carcinogenesis; comparative; comparative genomics; gene environment interaction; genetic analysis; genetic epidemiology; genetic linkage; genetic pedigree; genome wide association study; genome-wide; high risk; innovation; kindred; lung tumorigenesis; men; mortality; mouse model; novel; phenome; positional cloning; response; tobacco exposure; tool; trait; tumor

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify genetic modifiers of lung cancer induction. Although lung cancer is largely induced by smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. However, the identification of genetic factors underlying lung cancer induction in humans is impeded by limited genetic variation in human populations and by limitations in conducting genetic analysis in humans. Inbred mouse models offer an effective means of identifying candidate lung cancer susceptibility loci by using controlled mating as well as controlled tobacco exposure. The effectiveness of the inbred mouse model was demonstrated by genetic linkage studies using various strains of inbred mice by having mapped several pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci. With the increasing number of available mouse polymorphic genetic markers, genome- wide association (GWA) analysis has become an important genetic method to identify novel quantitative trait loci (QTL) and to fine-map previously identified QTL. We hypothesize that genetic modifiers for lung tumorigenesis can be identified using large populations of relevant individuals (mice or humans) and genome-wide set of single nucleotide polymorphisms (SNPs) for each subject. Three aims are proposed to accomplish our goal. In aim 1, we will conduct GWA analysis to map mouse lung tumor susceptibility QTL in response to tobacco smoke in 44 strains of mice using more than 190,000 SNP markers. In aim 2, we will examine human homologues of mouse susceptibility loci in high risk lung cancer families and sporadic lung cancer populations. Finally, these candidate genes indentified in Aim 2 will be further examined using funcational analyses in Aim 3. The significance of these studies is that they will identify human lung cancer genetic modifiers which confer increased risk of lung cancer and will help in developing mouse models relevant to these loci. The innovative aspect of this proposal is that we will examine the correlation between human and mouse susceptibility loci.

描述（由申请人提供）：该提案的长期目标是确定肺癌诱导的遗传修饰因子。尽管肺癌很大程度上是由吸烟诱发的，但有强有力的证据表明肺癌的发生与遗传易感性和基因-环境相互作用有关。然而，由于人群中有限的遗传变异以及在人类中进行遗传分析的局限性，对人类肺癌诱导遗传因素的识别受到阻碍。近交小鼠模型提供了一种通过控制交配和控制烟草暴露来识别候选肺癌易感位点的有效方法。通过使用各种近交小鼠品系的遗传连锁研究，通过绘制多个肺腺瘤易感性（Pas）和肺腺瘤抗性（Par）基因座，证明了近交小鼠模型的有效性。随着可用的小鼠多态性遗传标记数量的不断增加，全基因组关联（GWA）分析已成为识别新数量性状基因座（QTL）和精细定位先前识别的QTL的重要遗传方法。我们假设，可以使用大量相关个体（小鼠或人类）和每个受试者的全基因组单核苷酸多态性（SNP）来识别肺部肿瘤发生的遗传修饰因子。为了实现我们的目标，提出了三个目标。在目标 1 中，我们将使用超过 190,000 个 SNP 标记进行 GWA 分析，以绘制 44 种小鼠对烟草烟雾反应的小鼠肺肿瘤易感性 QTL。在目标 2 中，我们将检查高危肺癌家族和散发性肺癌人群中小鼠易感基因座的人类同源物。最后，目标 2 中确定的这些候选基因将使用目标 3 中的功能分析进行进一步检查。这些研究的意义在于，它们将确定导致肺癌风险增加的人类肺癌遗传修饰因子，并将有助于开发与这些位点相关的小鼠模型。该提案的创新之处在于我们将检查人类和小鼠易感位点之间的相关性。

项目成果

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• DOI: 10.1158/0008-5472.can-13-1617
• 发表时间: 2014-02-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: James MA;Vikis HG;Tate E;Rymaszewski AL;You M
• 通讯作者: You M

Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas.

• DOI: 10.1172/jci.insight.94220
• 发表时间: 2017-07
• 期刊: JCI insight
• 影响因子: 8
• 作者: Donghai Xiong;Jing Pan;Qi Zhang;E. Szabo;M. S. Miller;R. Lubet;Yian Wang;M. You

Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer.

• DOI: 10.1016/j.isci.2018.10.021
• 发表时间: 2018-11-30
• 期刊: iScience
• 影响因子: 5.8
• 作者: Xiong D;Wang Y;Singavi AK;Mackinnon AC;George B;You M
• 通讯作者: You M

Novel mutational landscapes and expression signatures of lung squamous cell carcinoma.

• DOI: 10.18632/oncotarget.23716
• 发表时间: 2018-01-26
• 期刊: Oncotarget
• 作者: Xiong D;Pan J;Yin Y;Jiang H;Szabo E;Lubet RA;Wang Y;You M
• 通讯作者: You M

26S proteasome activity is down-regulated in lung cancer stem-like cells propagated in vitro.

• DOI: 10.1371/journal.pone.0013298
• 发表时间: 2010-10-11
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pan J;Zhang Q;Wang Y;You M
• 通讯作者: You M