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: 10583526
• 负责人: Matthew Frank Buas
• 金额: $ 9.08万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583526
• 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; 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; 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.

项目摘要 /摘要 食道腺癌（EAC）是一种罕见但致命的癌症，中位生存期<1年。全基因组 协会研究（GWAS）估计EAC及其ITS的风险有很大的风险（25-35％） 前体，巴雷特的食道（BE）。已经发现了将近20个新型的遗传风险基因座，但大多数 遗传力仍然无法解释。 “缺少遗传力”阻碍了GWAS照亮分子的力量 疾病风险的途径并确定新的干预目标。在此提案中，我们寻求 克服对BE/EAC样本量的继承限制，并通过整合来识别新型敏感性局部 基于网络的先进方法和组织特异性的调节资源成生物学动机 发现框架。几条证据牵涉到BE/EAC生物学中的转录调节网络 以及使用基于网络的方法来探测该癌症未发现的遗传基础的动机。 这些发现包括在BE/EAC组织中重新激活关键的胚胎转录调节剂。躯体 EAC肿瘤中转录因子（TF）基因的基因组改变；和全基因组具有重要意义的GWA 信号与编码食道/foregut TF的基因非常接近。以这些观察为基础 普遍的观点，疾病连接的遗传变异在有限的核心生物学集合上功能收敛 途径，我们假设嵌入在发育转录网络中的遗传信号代表 BE/EAC的“缺少遗传力”的重要来源。使用定制的与疾病的参考网络 与GWAS衍生的节点权重覆盖，我们将筛选基因级别和增强子/启动子级遗传 先前全基因组扫描错过的关联。我们的多学科MPI团队借鉴了很强的轨道 在BE/EAC遗传学中记录，利用访问最大的GWAS数据集的访问以及广泛的OMICS 来自GTEX，路线图/编码和启动子捕获HIC的数据。在AIM 1中，我们将确定共表达的基因 使用源自RNA-Seq的转录调节网络，富含风险相关的遗传变异 概况。通过互信息和图形套索方法组装的共表达网络应用于 330个胃食管结构组织的转录组将带有基因级的重量 GWAS测试并使用层次热网（HHN）进行了分析。在AIM 2中，我们将确定链接的发起人和 使用3D染色质相互作用曲线的调节图具有浓缩GWAS信号的增强子。 将加载使用启动子捕获者数据构建的增强子目标参考网络，将加载在正常食道中 带有定制基于SNP的测试的权重，并通过HHN进行了评估。我们提出的研究将有助于 阐明EAC及其唯一已知的先驱（BE）的遗传结构。候选风险基因和 增强子/启动子将推进目前正在已知基因座的功能验证研究 通过持续的合作，目的是定义BE/EAC的新预防/治疗目标。