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

基本信息

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
项目类别：
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

项目摘要

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剂。尽管肺癌在很大程度上是由吸烟引起的，但有充分的证据表明遗传易感性和基因环境相互作用在肺癌的发展中。然而，人群的遗传差异有限以及人类进行遗传分析的局限性阻碍了人类肺癌诱导的遗传因素的鉴定。近交小鼠模型提供了一种有效的方法，可以通过使用受控的交配以及受控的烟草暴露来识别候选肺癌敏感性基因座。通过绘制了几种肺腺瘤易感性（PAS）和肺腺瘤耐药性（PAR）基因座，使用各种近交小鼠菌株的遗传连锁研究证明了近交小鼠模型的有效性。随着可用小鼠多态性遗传标记数量的增加，基因组广泛的缔合（GWA）分析已成为鉴定新的定量性状基因座（QTL）和对先前鉴定的QTL进行识别的重要遗传学方法。我们假设可以使用大量相关个体（小鼠或人）和全基因组的单核苷酸多态性（SNP）来鉴定肺肿瘤发生的遗传修饰剂。提出了三个目标来实现我们的目标。在AIM 1中，我们将对使用超过190,000个SNP标记的44种小鼠菌株中的烟草烟雾进行GWA分析，以绘制小鼠肺肿瘤易感性QTL。在AIM 2中，我们将研究高风险肺癌家族和零星肺癌种群中小鼠易感基因座的人类同源物。最后，将使用AIM 3中的弹性分析进一步研究这些缩进AIM 2中的候选基因。这些研究的重要性是，它们将鉴定人类肺癌遗传修饰剂，从而赋予肺癌的风险增加，并有助于开发与这些基因座相关的小鼠模型。该提案的创新方面是我们将研究人与小鼠敏感性基因座之间的相关性。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis.

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
通讯作者：
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.