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Grant Details

Grant Number: 5R01CA134682-06 Interpret this number
Primary Investigator: You, Ming
Organization: Medical College Of Wisconsin
Project Title: Genome-Wide Association Studies of Inherited Predisposition to Lung Cancer
Fiscal Year: 2013
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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.

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Publications

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, 2018-11-30; 9, p. 258-277.
EPub date: 2018-10-25.
PMID: 30439581
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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; 9(7), p. 7424-7441.
EPub date: 2017-12-27.
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; 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; 2(13), .
EPub date: 2017-07-06.
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; 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; 96(2), p. 301-8.
EPub date: 2015-01-29.
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.
EPub date: 2014-08-26.
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.
EPub date: 2014-03-13.
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.
EPub date: 2013-11-17.
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; 74(4), p. 1116-27.
EPub date: 2013-12-23.
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; 93(3), p. 439-51.
EPub date: 2013-08-15.
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.
EPub date: 2013-08-26.
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.
EPub date: 2012-06-13.
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.
EPub date: 2012-04-17.
PMID: 22510280
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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.
EPub date: 2012-08-09.
PMID: 22889990
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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.
EPub date: 2012-07-09.
PMID: 22808122
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Principal components analysis of population admixture.
Authors: Ma J. , Amos C.I. .
Source: PloS one, 2012; 7(7), p. e40115.
EPub date: 2012-07-09.
PMID: 22808102
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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; 5(10), p. e13298.
EPub date: 2010-10-11.
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; 70(8), p. 3128-35.
PMID: 20395203
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