Leveraging tissue-specific regulatory maps and network-assisted analysis to identify novel genetic risk loci for esophageal adenocarcinoma

利用组织特异性调控图和网络辅助分析来识别食管腺癌的新遗传风险位点

• 批准号: 10674212
• 负责人: Matthew Frank Buas
• 金额: $ 6.16万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-03 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674212
• 关键词: 3-Dimensional; Advanced Development; Area; Barrett Esophagus; Biological; Biological Assay; Biology; Chest; Chromatin; Collaborations; Coupled; Custom; DNA Sequence Alteration; Data; Data Set; Detection; Development; Disease; Embryo; Enhancers; Esophageal Adenocarcinoma; Esophagogastric Junction; Esophagus; Etiology; Expression Profiling; FOXF1 gene; FOXP1 gene; Future; GATA4 gene; Genes; Genetic; Genetic Research; Genetic Risk; Genetic Transcription; Genetic Variation; Genome Scan; Genotype-Tissue Expression Project; Goals; HNF4A gene; Heritability; Human; Inherited; International; Intervention; Laboratories; Lasso; Light; Link; MADH4 gene; Malignant Neoplasms; Maps; Methods; Molecular; Molecular Target; Mutation; Network-based; Pathway interactions; Positioning Attribute; Predisposition; Prevention strategy; Preventive; Primitive foregut structure; Public Health; Recurrence; Regulatory Element; Research; Resources; Risk; Role; Sample Size; Signal Transduction; Source; Statistical Methods; Susceptibility Gene; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Validation; Variant; Weight; Work; base; cancer genome; cost effective; disorder risk; genetic architecture; genetic association; genome sequencing; genome wide association study; genome-wide; interest; mortality; multidisciplinary; novel; preventive intervention; promoter; public health relevance; rare cancer; risk variant; sex; therapeutic target; transcription factor; transcription regulatory network; transcriptome; transcriptome sequencing; tumor; validation studies

PROJECT SUMMARY / ABSTRACT Esophageal adenocarcinoma (EAC) is a rare yet lethal cancer with median survival <1 year. Genome-wide association studies (GWAS) have estimated a substantial heritable component of risk (25-35%) for EAC and its precursor, Barrett’s esophagus (BE). Nearly 20 novel genetic risk loci have been discovered, but most heritability remains unexplained. ‘Missing heritability’ hinders the power of GWAS to illuminate molecular pathways underlying disease risk and identify novel targets for intervention. In this proposal, we seek to overcome inherent limits on sample sizes for BE/EAC and identify novel susceptibility loci by integrating advanced network-based methods and tissue-specific regulome resources into a biologically-motivated discovery framework. Several lines of evidence implicate transcriptional regulatory networks in BE/EAC biology and motivate use of network-based approaches to probe undiscovered genetic underpinnings of this cancer. These findings include reactivation of key embryonic transcriptional regulators in BE/EAC tissues; somatic genomic alterations in transcription factor (TF) genes in EAC tumors; and genome-wide-significant GWAS signals in close proximity to genes encoding esophageal/foregut TFs. Building on these observations, and the prevailing view that disease-linked genetic variation functionally converges on a limited set of core biological pathways, we hypothesize that genetic signals embedded in developmental transcriptional networks represent an important source of ‘missing heritability’ for BE/EAC. Using customized disease-relevant reference networks overlaid with GWAS-derived node weights, we will screen for gene-level and enhancer/promoter-level genetic associations missed by prior genome-wide scans. Our multi-disciplinary MPI team draws on a strong track record in BE/EAC genetics, leveraging access to the largest available GWAS datasets, and extensive omics data from GTEx, RoadMap/ENCODE, and promoter-capture HiC. In Aim 1, we will identify co-expressed genes enriched in risk-associated genetic variation, using transcriptional regulatory networks derived from RNA-seq profiles. Co-expression networks assembled via mutual information and graphical lasso methods applied to transcriptomes of 330 gastro-esophageal junction tissues will be populated with weights from gene-level GWAS tests, and analyzed using Hierarchical Hotnet (HHN). In Aim 2, we will identify linked promoters and enhancers with concentrated GWAS signal using regulatory maps from 3D chromatin interaction profiles. Enhancer-target reference networks built using promoter-capture-HiC data in normal esophagus will be loaded with weights from custom SNP-set-based tests and evaluated via HHN. Our proposed research will help elucidate the genetic architecture of EAC and its only known precursor (BE). Candidate risk genes and enhancers/promoters will be advanced to functional validation studies currently underway for known loci through an ongoing collaboration, with the goal of defining new preventive/therapeutic targets for BE/EAC.

项目概要/摘要 食管腺癌（EAC）是一种罕见但致命的癌症，中位生存期<1年。全基因组 关联研究 (GWAS) 估计了 EAC 及其相关风险的重要遗传成分 (25-35%)。 前体，巴雷特食管（BE）。已发现近 20 个新的遗传风险位点，但大多数 遗传性仍然无法解释。 “遗传性缺失”阻碍了 GWAS 阐明分子生物学的能力 潜在疾病风险的途径并确定新的干预目标。在本提案中，我们力求 克服 BE/EAC 样本量的固有限制，并通过整合识别新的易感性位点 先进的基于网络的方法和组织特异性调节组资源转化为生物驱动的 发现框架。多项证据表明 BE/EAC 生物学中的转录调控网络 并鼓励使用基于网络的方法来探索这种癌症未被发现的遗传基础。 这些发现包括 BE/EAC 组织中关键胚胎转录调节因子的重新激活；躯体的 EAC 肿瘤中转录因子 (TF) 基因的基因组改变；和全基因组显着性 GWAS 信号与编码食管/前肠 TF 的基因非常接近。在这些观察的基础上， 普遍的观点认为，与疾病相关的遗传变异在功能上集中在一组有限的核心生物学上 途径，我们假设嵌入发育转录网络中的遗传信号代表 BE/EAC“遗传缺失”的重要来源。使用定制的疾病相关参考网络 与 GWAS 衍生的节点权重重叠，我们将筛选基因水平和增强子/启动子水平遗传 先前的全基因组扫描遗漏了关联。我们的多学科 MPI 团队拥有强大的优势 BE/EAC 遗传学记录，利用最大的可用 GWAS 数据集和广泛的组学 来自 GTEx、RoadMap/ENCODE 和启动子捕获 HiC 的数据。在目标 1 中，我们将识别共表达基因 使用源自 RNA-seq 的转录调控网络，丰富了与风险相关的遗传变异 配置文件。通过互信息和图形套索方法组装的共表达网络应用于 330 个胃食管连接组织的转录组将使用基因水平的权重进行填充 GWAS 测试，并使用分层热网 (HHN) 进行分析。在目标 2 中，我们将识别关联的启动子和 使用来自 3D 染色质相互作用谱的调控图谱来识别具有集中 GWAS 信号的增强子。 将加载使用正常食道中的启动子捕获-HiC 数据构建的增强子目标参考网络 权重来自基于 SNP 集的自定义测试，并通过 HHN 进行评估。我们提出的研究将有助于 阐明 EAC 及其唯一已知前体 (BE) 的遗传结构。候选风险基因和 增强子/启动子将进入目前正在进行的已知基因座的功能验证研究 通过持续的合作，目标是为 BE/EAC 确定新的预防/治疗目标。