Project 1 - Genetic Predisposition To Barrett's Esophagus and Esophageal Adenocarcinoma

项目总结 Barrett‘s食道(BE)和食管腺癌(EAC)是尚未发现的复杂疾病 遗传因素。我们成功地在一个大家庭中发现了VSIG10L分离的有害变异。这 是第一个报道的易患BE和EAC的基因。VSIG10L似乎在黏附和 复层鳞状上皮的分化/成熟。关于基因基础的进一步线索来自我们的 混合作图研究，发现了与过量相关的两个特定染色体区域 非裔美国人的欧洲血统。因此，BETRNet项目1的重点是确定遗传病的遗传基础 BE和EAC患病率的种族差异。BETRNet项目1的第二个重点是创造一个基因上的 基于VSIG10L的工程化小鼠模型研究鳞状上皮向 化生的巴雷特上皮。该项目现在将通过以下方式建立在这些发现的基础上： 1)使用密集SNP基因分型、NextGen测序和ATAC-SEQ来识别不同种族的基因 解释BE和EAC患病率的种族差异的变体； 2)利用基因工程VSIG10L基因敲除和VSIG10L S631G变种携带小鼠 了解VSIG10L对正常鳞状上皮食管炎BE的作用 化生；异型增生；；癌进展； 项目1的意义是首先将BE和EAC的种族差异的临床观察转化为 实验室来确定致病的遗传基础。此外，该项目将建立在我们成功发现 通过了解该基因在化生组织中的作用，首次发现家族性易感基因变异 巴雷特上皮变性。

PROJECT SUMMARY Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are complex diseases with undiscovered genetic factors. We successfully discovered a deleterious variant in VSIG10L segregating in a large family. This is the first such reported gene for susceptibility to BE and EAC. VSIG10L appears to function in adhesion and differentiation/maturation of stratified squamous epithelium. Further clues for a genetic basis comes from our admixture mapping study, which has identified two specific chromosomal regions associated with excess European ancestry in African Americans. The BETRNet focus of Project 1 is thus to identify the genetic basis of racial disparity in the prevalence of BE and EAC. A second BETRNet focus of Project 1 is to create a genetically engineered mouse model based on VSIG10L to understand the transformation from squamous epithelium to metaplastic Barrett's epithelium. This project will now build on these discoveries by: 1) Using dense SNP genotyping, NextGen sequencing, and ATAC-seq to identify racially disparate genetic variants that explain racial differences in prevalence of BE and EAC; 2) Using genetically engineered VSIG10L knockout and VSIG10L S631G variant carrying mice to understand how VSIG10L contributes to the normal squamous epithelium  esophagitis  BE metaplasia  dysplasia  cancer progression; The significance of Project 1 is first to translate the clinical observation of racial disparity in BE and EAC into the laboratory to identify a causative genetic basis. Furthermore, the project will build on our successful discovery of the first familial susceptibility genetic variant by understanding how this gene functions in metaplastic transformation of Barrett's epithelium.