Grant Number:	1R01CA141769-01A2 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:	2011

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. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths and COPD is the 4th leading cause of death in adults; together they account for substantial mortality and morbidity with limited treatment options. This study will elucidate new pathways on which to focus treatment efforts and identify target populations for interventions and screening.




Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci.
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Association of Germline Pathogenic Variants in MUTYH and Other DNA Damage Response Genes With Lung Cancer Risk Among Non-Hispanic Whites and African Americans.
Authors: Trendowski M.R. , Lusk C.M. , Wenzlaff A.S. , Neslund-Dudas C. , Purrington K.S. , Beebe-Dimmer J.L. , Schwartz A.G. .
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Evaluation of the Immune Response within the Tumor Microenvironment in African American and Non-Hispanic White Patients with Non-Small Cell Lung Cancer.
Authors: Trendowski M.R. , Watza D. , Lusk C.M. , Lonardo F. , Ratliff V. , Wenzlaff A.S. , Mamdani H. , Neslund-Dudas C. , Boerner J.L. , Schwartz A.G. , et al. .
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Assessing a Polygenic Risk Score for Lung Cancer Susceptibility in Non-Hispanic White and Black Populations.
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ATR inhibition overcomes platinum tolerance associated with ERCC1- and p53-deficiency by inducing replication catastrophe.
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Lung Cancer Screening Criteria and Cardiopulmonary Comorbidities.
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Comparison Between the 2021 USPSTF Lung Cancer Screening Criteria and Other Lung Cancer Screening Criteria for Racial Disparity in Eligibility.
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Computed Tomography Features of Lung Structure Have Utility for Differentiating Malignant and Benign Pulmonary Nodules.
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Rare deleterious germline variants and risk of lung cancer.
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COPD-dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk.
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PMID: 31709530
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Circulating Inflammation Proteins Associated With Lung Cancer in African Americans.
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Machine learning approach for distinguishing malignant and benign lung nodules utilizing standardized perinodular parenchymal features from CT.
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Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer.
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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. .
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Quantitative Imaging Markers of Lung Function in a Smoking Population Distinguish COPD Subgroups with Differential Lung Cancer Risk.
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Post-imaging pulmonary nodule mathematical prediction models: are they clinically relevant?
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Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer.
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