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）：虽然食管腺癌（EAC）和食管胃结合部腺癌（EGJAC）的发病率持续上升，但预后仍然较差。尽管有关 EAC 和 Barrett 食管 (BE) 体细胞遗传学的数据不断积累，但 BE 和 EAC/EGJAC 遗传易感性的病因仍不清楚。对文献和我们自己的多学科、多中心小组（俄亥俄州家族性巴雷特食管联盟 (OFBEC)）的初步调查显示，大约 20% 的 BE 具有家族聚集性，其中包括 BE、EAC 和/或 EGJAC，并且遗传模式很可能是常染色体显性遗传。此外，PI 在 20 号染色体上有一个推定的易感位点，暗示与单一多重家族中的 BE/EAC 连锁。两个小家族与该假定基因座的连锁一致，而另外两个家族则没有连锁。因此，该提案将检验以下假设： 1. 至少存在2个易患BE/EAC的易感基因；和 2. 这些在家族性BE/EAC的种系易感性中发挥作用的易感基因是抑癌基因，在散发性BE和EAC的发生中也发挥一定作用。 首先，PI 将使用 400 个标记的常染色体基因组扫描来确认 20 号染色体连锁，并确定所有受影响家族中哪些部分与该假定基因座有连锁。同时，PI将寻找与FBE/EAC/EGJAC相关的其他推定基因座(loci)。其次，PI 将使用基于阵列的表达分析来寻找转录物表达过度或表达不足的基因，这些基因位于 20 号染色体的关键区间以及基因组扫描定义的新区域内。与这些区域的 LOH 分析一起，这将补充虚拟物理作图和候选基因分析，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。这可能有助于分子诊断和早期预测以及有针对性的监测和预防。

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