Genetic Etiologies of Esophageal Barrett's and Cancer

描述（由申请人提供）：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。尽管积累了关于EAC和Barrett食管（BE）的体细胞遗传学数据，但BE和EAC/EGJAC的遗传易感性的病因仍然未知。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协会（OFBEC））的初步调查显示，约20%的BE具有家族聚集性，包括BE、EAC和/或EGJAC，遗传模式最有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基因座，提示在一个单一的多重家族中与BE/EAC连锁。2个小家系与该位点连锁，另外2个家系不连锁。因此，本提案将检验以下假设： 1.存在至少两个易患BE/EAC的易感基因;并且 2.这些易感基因在家族性BE/EAC的种系易感性中起作用，它们是肿瘤抑制基因，在散发性BE和EAC的发生中也起一定作用。 首先，使用400个标记的常染色体基因组扫描，PI将试图确认20号染色体连锁，并将确定所有受影响的家庭中有多少部分与这个假定的基因座连锁。同时，PI将寻找与FBE/EAC/EGJAC连锁的其他推定基因座。其次，PI将使用基于阵列的表达分析来寻找其转录物过度表达或表达不足的基因，这些基因位于20号染色体的临界区间内以及基因组扫描定义的新区域内。结合这些区域的洛缺失分析，将为寻找BE/EAC/EGJAC家族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（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。

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.