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Grant Details

Grant Number: 1R01CA134682-01A2 Interpret this number
Primary Investigator: You, Ming
Organization: Washington University
Project Title: Genome-Wide Association Studies of Inherited Predisposition to Lung Cancer
Fiscal Year: 2009


Abstract

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. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death in men and women in the United States. Despite major advances in recent years, most lung cancers are disseminated at the time of presentation and have a mortality rate of about 90%. Studies of familial aggregation of lung cancer suggest that genetic factors are involved in human lung tumor development. This proposal will identify genetic modifiers of lung cancer induction using comparative genomic approaches. We anticipate the identification of human lung cancer genetic modifiers which confer increased risk of lung cancer through the proposed cross-species studies between human and mouse susceptibility loci.



Publications

Rare deleterious germline variants and risk of lung cancer.
Authors: Liu Y. , Xia J. , McKay J. , Tsavachidis S. , Xiao X. , Spitz M.R. , Cheng C. , Byun J. , Hong W. , Li Y. , et al. .
Source: Npj Precision Oncology, 2021-02-16 00:00:00.0; 5(1), p. 12.
EPub date: 2021-02-16 00:00:00.0.
PMID: 33594163
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miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer.
Authors: Parashar D. , Geethadevi A. , Aure M.R. , Mishra J. , George J. , Chen C. , Mishra M.K. , Tahiri A. , Zhao W. , Nair B. , et al. .
Source: Cell Reports, 2019-12-24 00:00:00.0; 29(13), p. 4389-4406.e10.
PMID: 31875548
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Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer.
Authors: Xiong D. , Wang Y. , Singavi A.K. , Mackinnon A.C. , George B. , You M. .
Source: Iscience, 2018-10-25 00:00:00.0; 9, p. 258-277.
EPub date: 2018-10-25 00:00:00.0.
PMID: 30439581
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Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.
Authors: Liu Y. , Lusk C.M. , Cho M.H. , Silverman E.K. , Qiao D. , Zhang R. , Scheurer M.E. , Kheradmand F. , Wheeler D.A. , Tsavachidis S. , et al. .
Source: Journal Of Thoracic Oncology : Official Publication Of The International Association For The Study Of Lung Cancer, 2018 Oct; 13(10), p. 1483-1495.
EPub date: 2018-07-04 00:00:00.0.
PMID: 29981437
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Novel mutational landscapes and expression signatures of lung squamous cell carcinoma.
Authors: Xiong D. , Pan J. , Yin Y. , Jiang H. , Szabo E. , Lubet R.A. , Wang Y. , You M. .
Source: Oncotarget, 2018-01-26 00:00:00.0; 9(7), p. 7424-7441.
EPub date: 2017-12-27 00:00:00.0.
PMID: 29484121
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Corrupting the DNA damage response: a critical role for Rad52 in tumor cell survival.
Authors: Lieberman R. , You M. .
Source: Aging, 2017-07-15 00:00:00.0; 9(7), p. 1647-1659.
PMID: 28722656
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Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas.
Authors: Xiong D. , Pan J. , Zhang Q. , Szabo E. , Miller M.S. , Lubet R.A. , Wang Y. , You M. .
Source: Jci Insight, 2017-07-06 00:00:00.0; 2(13), .
EPub date: 2017-07-06 00:00:00.0.
PMID: 28679956
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Bronchial Airway Gene Expression Signatures In Mouse Lung Squamous Cell Carcinoma And Their Modulation By Cancer Chemopreventive Agents
Authors: Xiong D. , Pan J. , Zhang Q. , Szabo E. , Miller M.S. , Lubet R.A. , You M. , Wang Y. .
Source: Oncotarget, 2017-03-21 00:00:00.0; 8(12), p. 18885-18900.
PMID: 27935865
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Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.
Authors: Liu Y. , Kheradmand F. , Davis C.F. , Scheurer M.E. , Wheeler D. , Tsavachidis S. , Armstrong G. , Simpson C. , Mandal D. , Kupert E. , et al. .
Source: Journal Of Thoracic Oncology : Official Publication Of The International Association For The Study Of Lung Cancer, 2016 Jan; 11(1), p. 52-61.
PMID: 26762739
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A recurrent mutation in PARK2 is associated with familial lung cancer.
Authors: Xiong D. , Wang Y. , Kupert E. , Simpson C. , Pinney S.M. , Gaba C.R. , Mandal D. , Schwartz A.G. , Yang P. , de Andrade M. , et al. .
Source: American Journal Of Human Genetics, 2015-02-05 00:00:00.0; 96(2), p. 301-8.
EPub date: 2015-02-05 00:00:00.0.
PMID: 25640678
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Bayesian variable selection for hierarchical gene-environment and gene-gene interactions.
Authors: Liu C. , Ma J. , Amos C.I. .
Source: Human Genetics, 2015 Jan; 134(1), p. 23-36.
PMID: 25154630
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Genome-wide association tests of inversions with application to psoriasis.
Authors: Ma J. , Xiong M. , You M. , Lozano G. , Amos C.I. .
Source: Human Genetics, 2014 Aug; 133(8), p. 967-74.
PMID: 24623382
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Natural and orthogonal model for estimating gene-gene interactions applied to cutaneous melanoma.
Authors: Xiao F. , Ma J. , Cai G. , Fang S. , Lee J.E. , Wei Q. , Amos C.I. .
Source: Human Genetics, 2014 May; 133(5), p. 559-74.
PMID: 24241239
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Crr9/clptm1l Regulates Cell Survival Signaling And Is Required For Ras Transformation And Lung Tumorigenesis
Authors: James M.A. , Vikis H.G. , Tate E. , Rymaszewski A.L. , You M. .
Source: Cancer Research, 2014-02-15 00:00:00.0; 74(4), p. 1116-27.
PMID: 24366883
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DrGaP: a powerful tool for identifying driver genes and pathways in cancer sequencing studies.
Authors: Hua X. , Xu H. , Yang Y. , Zhu J. , Liu P. , Lu Y. .
Source: American Journal Of Human Genetics, 2013-09-05 00:00:00.0; 93(3), p. 439-51.
EPub date: 2013-09-05 00:00:00.0.
PMID: 23954162
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A unified framework integrating parent-of-origin effects for association study.
Authors: Xiao F. , Ma J. , Amos C.I. .
Source: Plos One, 2013; 8(8), p. e72208.
PMID: 23991061
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Exome sequencing identifies MXRA5 as a novel cancer gene frequently mutated in non-small cell lung carcinoma from Chinese patients.
Authors: Xiong D. , Li G. , Li K. , Xu Q. , Pan Z. , Ding F. , Vedell P. , Liu P. , Cui P. , Hua X. , et al. .
Source: Carcinogenesis, 2012 Sep; 33(9), p. 1797-805.
PMID: 22696596
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Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing.
Authors: Liu P. , Morrison C. , Wang L. , Xiong D. , Vedell P. , Cui P. , Hua X. , Ding F. , Lu Y. , James M. , et al. .
Source: Carcinogenesis, 2012 Jul; 33(7), p. 1270-6.
PMID: 22510280
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Principal components analysis of population admixture.
Authors: Ma J. , Amos C.I. .
Source: Plos One, 2012; 7(7), p. e40115.
PMID: 22808102
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Investigation of inversion polymorphisms in the human genome using principal components analysis.
Authors: Ma J. , Amos C.I. .
Source: Plos One, 2012; 7(7), p. e40224.
PMID: 22808122
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Natural and orthogonal interaction framework for modeling gene-environment interactions with application to lung cancer.
Authors: Ma J. , Xiao F. , Xiong M. , Andrew A.S. , Brenner H. , Duell E.J. , Haugen A. , Hoggart C. , Hung R.J. , Lazarus P. , et al. .
Source: Human Heredity, 2012; 73(4), p. 185-94.
PMID: 22889990
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26S proteasome activity is down-regulated in lung cancer stem-like cells propagated in vitro.
Authors: Pan J. , Zhang Q. , Wang Y. , You M. .
Source: Plos One, 2010-10-11 00:00:00.0; 5(10), p. e13298.
EPub date: 2010-10-11 00:00:00.0.
PMID: 20949018
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A second genetic variant on chromosome 15q24-25.1 associates with lung cancer.
Authors: Liu P. , Yang P. , Wu X. , Vikis H.G. , Lu Y. , Wang Y. , Schwartz A.G. , Pinney S.M. , de Andrade M. , Gazdar A. , et al. .
Source: Cancer Research, 2010-04-15 00:00:00.0; 70(8), p. 3128-35.
PMID: 20395203
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