Genetic Etiologies of Esophageal Barrett's and Cancer

食管 Barrett 病和癌症的遗传病因

• 批准号: 6663083
• 负责人: Charis Eng
• 金额: $ 12.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663083
• 关键词: Barretts esophagus; adenocarcinoma; autosomal dominant trait; chromosomes; clinical research; disease /disorder proneness /risk; esophagogastric junction disorder; esophagus neoplasm; family genetics; gene expression; genetic mapping; genetic susceptibility; human tissue; loss of heterozygosity; neoplasm /cancer genetics; polymerase chain reaction; tumor suppressor genes

DESCRIPTION (provided by applicant): While the incidence of adenocarcinomas of the esophagus (EAC) and of the esophagogastric junction (EGJAC) continue to rise, the prognosis remains poor. Despite the accumulation of data regarding the somatic genetics of EAC and Barrett esophagus (BE), the etiology of genetic predisposition to BE and EAC/EGJAC is still unknown. Preliminary investigations in the literature and our own multi-disciplinary, multi-center group, the Ohio Familial Barrett Esophagus Consortium (OFBEC), have revealed that approximately 20% of BE have familial aggregations which comprise BE, EAC and/or EGJAC, and that the inheritance pattern is most likely autosomal dominant. Further, the PI has a putative susceptibility locus on chromosome 20 with suggestion of linkage to BE/EAC in a single multiplex family. Two small families are consistent with linkage to this putative locus and 2 others are not linked. This proposal will, therefore, test the hypotheses: 1. There exist at least two susceptibility genes predisposing to BE/EAC; and 2. These susceptibility genes that play a role in germline predisposition to familial BE/EAC are tumor suppressor genes which also play some rote in the genesis of sporadic BE and EAC. First, using a 400-marker autosomal genome scan, the PI will seek to confirm the chromosome 20 linkage and will determine what fraction of all affected families are linked to this putative locus. At the same time, the PI will seek the other putative locus (loci) which is linked to FBE/EAC/EGJAC. Second, the PI will use array-based expression analysis to look for genes whose transcripts are over- or under-expressed that reside within the critical interval in chromosome 20 as well as within novel regions defined by genome scan. Together with LOH analysis in these regions, this will supplement virtual physical mapping and candidate gene analysis in searching for the susceptibility genes for familial BE/EAC/EGJAC. If successful, this project promises to yield clues to the genetic etiology (and hence genetic risk) for BE, EAC and EGJAC. This might facilitate molecular diagnostics and early prediction as well as targeted surveillance and prophylaxis.

描述（由申请人提供）：虽然食道（EAC）和食管胃结（EGJAC）的腺癌的发生率不断上升，但预后仍然很差。尽管数据积累了有关EAC和Barrett食管（BE）的体细胞遗传学的数据，但遗传易感性和EAC/EGJAC的病因仍然未知。文献中的初步研究以及我们自己的多学科多中心群体，俄亥俄州家族性的巴雷特食管联盟（OFBEC），已经显示，大约20％的BE具有家族性聚集，其中包含EAC和/或EGJAC，并且继承模式是最可能的自身瘤模式。此外，PI在20号染色体上具有假定的敏感性基因座，并建议单个多重族中的键为/eac。两个小家庭与与这个推定的基因座的联系一致，而另外两个则没有联系。因此，该建议将检验假设： 1。至少有两个易感基因易于be/eac；和 2。在家族性BE/EAC中发挥种系倾向的这些易感基因是肿瘤抑制基因，在零星BE和EAC的起源中也有一些死记硬背。 首先，使用400标记的常染色体基因组扫描，PI将寻求确认20号染色体连接，并将确定所有受影响家庭中的哪一部分与该假定基因座相关联。同时，PI将寻求与FBE/EAC/EGJAC相关的其他推定基因座（位点）。其次，PI将使用基于阵列的表达分析来寻找其转录本的过度表达或表达不足的基因，这些基因位于20号染色体的关键间隔以及基因组扫描定义的新区域中。与这些区域中的LOH分析一起，这将补充虚拟物理映射和候选基因分析，以寻找家族性BE/EAC/EGJAC的易感基因。如果成功，该项目有望为BE，EAC和EGJAC的遗传病因（以及遗传风险）提供线索。这可能促进分子诊断和早期预测以及靶向监视和预防。

项目成果

Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma.

• DOI: 10.1001/jama.2011.1029
• 发表时间: 2011-07-27
• 期刊: JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
• 影响因子: 120.7
• 作者: Orloff, Mohammed;Peterson, Charissa;He, Xin;Ganapathi, Shireen;Heald, Brandie;Yang, Yi-ran;Bebek, Gurkan;Romigh, Todd;Song, Jee Hoon;Wu, Wenjing;David, Stefan;Cheng, Yulan;Meltzer, Stephen J.;Eng, Charis
• 通讯作者: Eng, Charis