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Grant Details

Grant Number: 4R01CA141769-06 Interpret this number
Primary Investigator: Schwartz, Ann
Organization: Wayne State University
Project Title: Inflammation Pathways and Copd in the Development of Lung Cancer
Fiscal Year: 2016
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Abstract

DESCRIPTION (provided by applicant): Smoking contributes to a multitude of chronic diseases, including chronic obstructive lung disease (COPD) and lung cancer; approximately 15% of smokers will develop these diseases. The link between COPD and lung cancer has been demonstrated in epidemiologic studies, as well as family studies suggesting a common underlying genetic contribution to these diseases. The biologic mechanisms linking COPD and lung cancer are unknown, however chronic inflammation is likely to play a role. We propose to evaluate SNPs and copy number variation in genes in inflammatory pathways. The proposed study will expand on previous work by incorporating COPD phenotyping using CT diagnosis of emphysema and pulmonary function testing (PFT). It also will expand on the panel of genes beyond those few already evaluated, will incorporate copy number variation as well as non-synonymous and functional SNPs, and will include a large African American population. There has not been a study of these pathway genes in African Americans, a group that is less likely to report COPD, smokes fewer cigarettes, but is more likely to be diagnosed with lung cancer than whites. Specifically, from two large, urban health systems we will recruit 2050 lung cancer cases, 2050 smokers, and 600 patients with COPD. Approximately 46% of subjects will be African American. Each subject will complete a risk factor questionnaire, undergo CTs and PFTs, provide a blood sample, and when available a tissue block. It is hypothesized that genetic variation in inflammation-related genes contributes to the development of lung cancer and this association varies by the presence or absence of COPD, and by race. The goal is to develop a genetic profile based on SNPs and copy number variation in inflammation pathway genes that predicts susceptibility to lung cancer with and without COPD in response to tobacco exposure. In addition, gene expression of a panel of 370 inflammatory pathway genes will be evaluated in normal lung tissue in a subset of 250 cases with and 250 cases without a COPD diagnosis. No other large collection of cases is available that includes detailed phenotyping of lung cancer and COPD and jointly evaluates inflammatory genes in germline DNA and target tissue in the same individuals. This work will lead to a better understanding of the inflammatory process in lung carcinogenesis, provide avenues for the identification of a high risk group for intervention, and provide insight into possible treatment options.

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Publications

Profiling the Mutational Landscape in Known Driver Genes and Novel Genes in African American Non-Small Cell Lung Cancer Patients.
Authors: Lusk C.M. , Watza D. , Dyson G. , Craig D. , Ratliff V. , Wenzlaff A.S. , Lonardo F. , Bollig-Fischer A. , Bepler G. , Purrington K. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-07-15; 25(14), p. 4300-4308.
EPub date: 2019-04-12.
PMID: 30979741
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Machine learning approach for distinguishing malignant and benign lung nodules utilizing standardized perinodular parenchymal features from CT.
Authors: Uthoff J. , Stephens M.J. , Newell J.D. , Hoffman E.A. , Larson J. , Koehn N. , De Stefano F.A. , Lusk C.M. , Wenzlaff A.S. , Watza D. , et al. .
Source: Medical physics, 2019 Jul; 46(7), p. 3207-3216.
EPub date: 2019-06-07.
PMID: 31087332
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Circulating Inflammation Proteins Associated With Lung Cancer in African Americans.
Authors: Meaney C.L. , Mitchell K.A. , Zingone A. , Brown D. , Bowman E. , Yu Y. , Wenzlaff A.S. , Neslund-Dudas C. , Pine S.R. , Cao L. , et al. .
Source: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019 Jul; 14(7), p. 1192-1203.
EPub date: 2019-04-03.
PMID: 30953795
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Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer.
Authors: Heyza J.R. , Lei W. , Watza D. , Zhang H. , Chen W. , Back J.B. , Schwartz A.G. , Bepler G. , Patrick S.M. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-04-15; 25(8), p. 2523-2536.
EPub date: 2018-12-11.
PMID: 30538112
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Post-imaging pulmonary nodule mathematical prediction models: are they clinically relevant?
Authors: Uthoff J. , Koehn N. , Larson J. , Dilger S.K.N. , Hammond E. , Schwartz A. , Mullan B. , Sanchez R. , Hoffman R.M. , Sieren J.C. , et al. .
Source: European radiology, 2019-04-01; , .
EPub date: 2019-04-01.
PMID: 30937590
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Quantitative Imaging Markers of Lung Function in a Smoking Population Distinguish COPD Subgroups with Differential Lung Cancer Risk.
Authors: Lusk C.M. , Wenzlaff A.S. , Watza D. , Sieren J.C. , Robinette N. , Walworth G. , Petrich M. , Neslund-Dudas C. , Flynn M.J. , Song T. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 Apr; 28(4), p. 724-730.
EPub date: 2019-01-14.
PMID: 30642838
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Prognostic modeling of the immune-centric transcriptome reveals interleukin signaling candidates contributing to differential patient outcomes.
Authors: Watza D. , Lusk C.M. , Dyson G. , Purrington K.S. , Chen K. , Wenzlaff A.S. , Ratliff V. , Neslund-Dudas C. , Bepler G. , Schwartz A.G. .
Source: Carcinogenesis, 2018-12-31; 39(12), p. 1447-1454.
PMID: 30202894
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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 10; 13(10), p. 1483-1495.
EPub date: 2018-07-04.
PMID: 29981437
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Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis.
Authors: Schwartz A.G. , Lusk C.M. , Wenzlaff A.S. , Watza D. , Pandolfi S. , Mantha L. , Cote M.L. , Soubani A.O. , Walworth G. , Wozniak A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2016 09; 25(9), p. 1341-7.
EPub date: 2016-07-06.
PMID: 27383774
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Whole-exome sequencing reveals genetic variability among lung cancer cases subphenotyped for emphysema.
Authors: Lusk C.M. , Wenzlaff A.S. , Dyson G. , Purrington K.S. , Watza D. , Land S. , Soubani A.O. , Gadgeel S.M. , Schwartz A.G. .
Source: Carcinogenesis, 2016 Feb; 37(2), p. 139-144.
EPub date: 2015-12-30.
PMID: 26717996
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Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer.
Authors: Läubli H. , Pearce O.M. , Schwarz F. , Siddiqui S.S. , Deng L. , Stanczak M.A. , Deng L. , Verhagen A. , Secrest P. , Lusk C. , et al. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2014-09-30; 111(39), p. 14211-6.
EPub date: 2014-09-15.
PMID: 25225409
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Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.
Authors: Walsh K.M. , Gorlov I.P. , Hansen H.M. , Wu X. , Spitz M.R. , Zhang H. , Lu E.Y. , Wenzlaff A.S. , Sison J.D. , Wei C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013 Feb; 22(2), p. 251-60.
EPub date: 2012-12-05.
PMID: 23221128
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