Genetic Etiologies of Esophageal Barrett's and Cancer

描述(申请人提供)：虽然食管腺癌(EAC)和食管胃交界处腺癌(EGJAC)的发病率持续上升，但预后仍然很差。尽管有关EAC和Barrett食道(BE)的体细胞遗传学资料已经积累，但BE和EAC/EGJAC的遗传易感性仍不清楚。对文献和我们自己的多学科、多中心的俄亥俄州家族性Barrett食道联合会(OFBEC)的初步调查显示，大约20%的BE有家族聚集性，包括BE、EAC和/或EGJAC，遗传模式很可能是常染色体显性遗传。此外，PI在20号染色体上有一个可能的易感基因，推测连锁为BE/EAC在一个多重家系中。两个小家系与该推测的基因座连锁，另外两个家系没有连锁。因此，这项提议将检验以下假设： 1.至少存在两个易感BE/EAC的基因； 2.这些在家族性BE/EAC的遗传易感性中起作用的易感基因是肿瘤抑制基因，在散发性BE和EAC的发生中也起着一定的作用。 首先，利用400个标记的常染色体基因组扫描，PI将寻求确认20号染色体的连锁，并将确定所有受影响的家庭中有多大比例与这个假定的基因座有关。同时，PI还将寻找与FBE/EAC/EGJAC连锁的另一个可能的基因座。其次，PI将使用基于阵列的表达分析来寻找其转录过高或过低的基因，这些基因位于20号染色体的关键区间内，以及在基因组扫描定义的新区域内。结合这些区域的杂合性缺失分析，将为寻找家族性BE/EAC/EGJAC易感基因提供虚拟物理作图和候选基因分析的补充。如果成功，该项目有望为BE、EAC和EGJAC的遗传病因学(从而遗传风险)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。

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.