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

通过整合多组学数据鉴定肺癌风险基因和 DNA 甲基化标记

• 批准号: 10331874
• 负责人: QIUYIN CAI
• 金额: $ 67.57万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-22 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331874
• 关键词: Attenuated; Biological; Biological Assay; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Patient; Cessation of life; Chest; Country; DNA Methylation; Data; Data Set; Development; Disease susceptibility; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Translation; Genetic Variation; Genomics; Genotype; Genotype-Tissue Expression Project; IRF4 gene; Immune response; In Vitro; Lead; Lung Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Methodology; Methylation; Modeling; Multiomic Data; Normal tissue morphology; Patients; Phenotype; Pilot Projects; Play; Prevention; Reporting; Risk; Role; Sample Size; Series; Site; Structure of parenchyma of lung; Susceptibility Gene; System; The Cancer Genome Atlas; Tissue Sample; Tissues; Translating; Tumor Tissue; United States; Variant; biobank; biomarker discovery; cancer genetics; cancer risk; case control; causal variant; cost; cost efficient; density; disorder prevention; disorder risk; epigenetic variation; functional genomics; gene function; gene therapy; genetic variant; genome wide association study; genomic data; genomic locus; improved; in vitro Assay; innovation; instrument; lung cancer screening; lung carcinogenesis; malignant breast neoplasm; methylation biomarker; methylome; methylomics; novel; novel strategies; personalized medicine; predictive modeling; programs; risk variant; transcriptome; transcriptome sequencing; transcriptomics; tumor

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 ~55 genetic loci associated with lung cancer risk. However, causal genes (and their underlying biological mechanisms) for most of these loci remain unknown. Gene expression is an intermediate phenotype between genetic variants and disease. DNA methylation plays a critical role in regulating gene expression. Directly integrating genomic, transcriptomic, and methylomic data with disease risk can uncover novel disease susceptibility genes and potential mechanisms. However, it is extremely difficult, if at all possible, and costly to directly profile the transcriptome and methylome in lung tissues from a large number of cases and controls for evaluating 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 novel approaches have been shown to be very powerful 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. We propose to conduct a well-powered TWAS and MeWAS to discover novel genes and methylation loci (both potential targeted genes/methylation sites in GWAS-identified loci and genes/methylation sites in loci not yet uncovered by GWAS) for lung cancer risk (Aim 1). We will evaluate the differences in the expression levels of TWAS-identified genes and the 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 (Aim 2). We will investigate the regulating effects of methylation sites on the expression of promising genes and evaluate the functions of genes and methylation loci by functional genomics analyses (Aim 3). Finally, we will perform a serial of functional analyses to evaluate the potential functions of identified genes and methylation loci (Aim 4). 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 understanding of biological mechanisms. The proposed study is highly innovative and cost efficient. Our results will help us to better understand the mechanistic relationship between genetic and epigenetic variations and how those variations relate to lung cancer risk, and 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.

项目摘要 肺癌是美国和许多其他国家癌症死亡的主要原因。 全基因组关联研究（GWAS）已经确定了与肺癌风险相关的〜55个遗传基因座。 然而，这些基因座大多数的因果基因（及其潜在的生物学机制）仍然未知。 基因表达是遗传变异和疾病之间的中间表型。 DNA甲基化玩具 在调节基因表达中的关键作用。直接整合基因组，转录组和甲基甲基学数据 疾病风险可以发现新颖的疾病敏感性基因和潜在的机制。但是，是 极其困难（如果可能的话 来自大量病例和对照来评估这些关联的组织。在这里，我们提出了一个 新方法：整个转录组联想研究（TWA）和甲基化关联研究 （MEWAS）使用遗传仪器鉴定与肺癌风险有关的新型基因和甲基化基因座。 这些新颖的方法已被证明在识别新型基因和甲基化位点非常有力 在GWAS报告的基因座和GWAS中尚未揭示的地区，包括我们的飞行员在内 肺癌研究。我们建议进行一个能力供电的双子和Mewas，以发现新颖的基因和 甲基化基因座（GWAS识别基因座和基因/甲基化的潜在靶向基因/甲基化位点 GWAS尚未发现肺癌风险的位置的地点（AIM 1）。我们将评估 Twas识别基因的表达水平和肺之间的MEWAS识别基因座的甲基化水平 癌组织和正常组织，优先考虑可能有助于肺癌的基因和甲基化基因座 风险（目标2）。我们将研究甲基化位点对有希望表达的调节作用 基因并通过功能基因组学分析评估基因和甲基化基因座的功能（AIM 3）。 最后，我们将执行功能分析的序列，以评估已识别基因的潜在功能和 甲基化基因座（AIM 4）。我们预计这项拟议的研究将确定大量新基因，并且 用于肺癌风险的甲基化基因座，并提供功能数据以提高对生物学的了解 机制。拟议的研究具有高度创新性和成本效益。我们的结果将帮助我们更好 了解遗传和表观遗传变异之间的机械关系以及如何变化 与肺癌风险有关，并可能导致发现生物标志物，以促进早期发现 肺癌和用于个性化治疗的靶向基因疗法的发展。