R01CA249863

Identification of Genes and DNA Methylation Markers for Lung Cancer Risk by Integrating Multi-Omics Data - Project Summary

Lung cancer is the leading cause of cancer death in the United States and many other countries. Genome-wide association studies (GWAS) have identified approximately 55 genetic loci associated with lung cancer risk. However, the causal genes and their underlying biological mechanisms for most of these loci remain unknown.

Gene expression serves as an intermediate phenotype between genetic variants and disease. DNA methylation plays a critical role in regulating gene expression. By directly integrating genomic, transcriptomic, and methylomic data with disease risk, we can uncover novel disease susceptibility genes and potential mechanisms. However, it is extremely difficult, if not impossible, and costly to directly profile the transcriptome and methylome in lung tissues from a large number of cases and controls to evaluate these associations.

Herein, we propose a novel approach: Transcriptome-Wide Association Study (TWAS) and Methylation-Wide Association Study (MEWAS) to identify novel genes and methylation loci related to lung cancer risk using genetic instruments. These innovative approaches have demonstrated great power in identifying novel genes and methylation sites in both GWAS-reported loci and regions not yet revealed in GWAS in multiple recent studies, including our pilot study in lung cancer.

Our proposed study aims to conduct a well-powered TWAS and MEWAS to discover novel genes and methylation loci for lung cancer risk. This includes potential targeted genes/methylation sites in GWAS-identified loci, as well as genes/methylation sites in loci not yet uncovered by GWAS. Additionally, we will evaluate the differences in expression levels of TWAS-identified genes and methylation levels of MEWAS-identified loci between lung cancer tissues and normal tissues to prioritize genes and methylation loci that may contribute to lung cancer risk.

Furthermore, we will investigate the regulating effects of methylation sites on the expression of promising genes and evaluate the functions of genes and methylation loci through functional genomics analyses. Finally, we will perform a series of functional analyses to evaluate the potential functions of the identified genes and methylation loci.

We anticipate that this proposed study will identify a large number of novel genes and methylation loci for lung cancer risk and provide functional data to improve our understanding of biological mechanisms. The proposed study is highly innovative and cost-efficient. Our results will help us better understand the mechanistic relationship between genetic and epigenetic variations and how those variations relate to lung cancer risk. Additionally, our findings may lead to the discovery of biomarkers that would facilitate early detection of lung cancer and the development of targeted gene therapies for personalized treatment.

Vanderbilt University Medical Center

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Nashville, Tennessee 37203 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 361% from $732,586 to $3,377,653.