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

项目概要 巴雷特食管 (BE) 和食管腺癌 (EAC) 是尚未发现的复杂疾病 遗传因素。我们成功地发现了 VSIG10L 中的一个有害变异，该变异在一个大家族中分离。这个 是第一个报道的 BE 和 EAC 易感性基因。 VSIG10L 似乎在粘附和 复层鳞状上皮的分化/成熟。遗传基础的进一步线索来自我们 混合图谱研究，确定了与过量相关的两个特定染色体区域 非裔美国人有欧洲血统。因此，BETRNet 项目 1 的重点是确定 BE 和 EAC 患病率的种族差异。项目 1 的第二个 BETRNet 重点是创建一个基因 基于 VSIG10L 的工程小鼠模型，以了解从鳞状上皮到 化生巴雷特上皮。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 来识别种族不同的遗传 解释 BE 和 EAC 患病率种族差异的变体； 2）利用基因工程VSIG10L敲除和VSIG10L S631G变体携带小鼠 了解 VSIG10L 如何促进正常鳞状上皮  食管炎  BE 化生→不典型增生→癌症进展； 项目1的意义首先是将BE和EAC种族差异的临床观察转化为 实验室确定致病遗传基础。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中的功能，第一个家族易感性遗传变异 Barrett 上皮细胞的转化。

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.