Genomic studies for understanding etiology of esophageal adenocarcinoma

 描述（由申请人提供）：食管癌是全球第八大常见癌症，也是癌症相关死亡的第六大原因。食管癌的发病率因组织学和地理区域而异。在过去的四十年中，美国（US）的主要组织学类型已从食管鳞状细胞癌（ESCC）急剧转变为食管腺癌（EA）。然而，在中国及其周边地区，ESCC是主要类型; EA仍然罕见，与Barrett食管（BE）无关。虽然预防和治疗策略是迫切需要的，EA病因的遗传和环境结构，这种深刻的时间，空间和组织学的变化仍然不清楚。 最近的高通量基因组学研究在理解EA的种系和体细胞突变方面取得了进展。对于理解EA的遗传基础仍然存在重大差距。首先，遗传易感性位点如何与已经研究了20多年的风险因素相结合，对EA的风险预测做出贡献？其次，考虑到大多数体细胞突变已经发生在BE中，并且大多数BE病例不会进展为EA，那么驱动EA致癌的突变基因是什么？ 在这个项目中，我们建议利用现有的全基因组关联数据和癌症基因组数据进行基因组研究，以了解食管腺癌的病因。将采取一些创新的方法，包括种系和体细胞突变的综合分析，基因-环境相互作用的全基因组搜索，以及中美之间的比较基因组学。最终目标是发现遗传标记，包括生殖系和体细胞突变，用于食管腺癌的早期检测和治疗。

 DESCRIPTION (provided by applicant): Esophageal carcinoma is the eighth most common cancer and the sixth leading cause of cancer-related mortality worldwide. The incidence of esophageal cancer varies widely by histology and geographic region. Over the past four decades, the predominant histological type in the United States (US) has shifted drastically from esophageal squamous-cell carcinoma (ESCC) to esophageal adenocarcinoma (EA). In China and its surrounding areas, however, ESCC is the predominant type; EA remains rare without association of Barrett's esophagus (BE). While prevention and therapeutic strategies are urgently needed, the genetic and environmental architecture of EA etiology that underwrites this profound temporal, spatial and histological variation remains unclear. Recent high-throughput genomic studies have made progress in understanding germline and somatic mutations of EA. Significant gaps remain for understanding genetic basis of EA. First, how do genetic susceptibility loci contribute to risk prediction for EA, in concert with the risk factors that hav been studied for over 20 years? Second, what are mutated genes that drive carcinogenesis of EA, given the majority of somatic mutations already occur in BE and most BE cases do not progress to EA? In this project, we propose genomic studies for understanding the etiology of esophageal adenocarcinoma, leveraging existing genome-wide association data and cancer genome data. A number of innovative approaches will be undertaken include integrative analyses of germline and somatic mutations, genome-wide searching for gene-environment interaction, and comparative genomics between US and China. The ultimate goal is to dis- cover genetic markers, both germline and somatic mutations, for early detection and treatment of esophageal adenocarcinoma.