A minimal critical region of the 8p22-23 amplicon in esophageal adenocarcinomas defined using sequence tagged site-amplification mapping and quantitative polymerase chain reaction includes the GATA-4 gene

The incidence of esophageal adenocarcinomas has increased greatly over the past 20 years. The genetic alterations associated with this disease, howeve r, remain largely unknown. We identified recently a novel amplicon at 8p22- 23 in esophageal adenocarcinomas using the restriction landmark genomic sca nning two-dimensional gel technique, Four known genes within or near this a mplicon were initially characterized. The cathepsin B (CTSB) gene was found to be amplified in 13% of esophageal tumors, CTSB was shown previously to be overexpressed without amplification in many other human cancers. An appr oach termed sequence tagged site-amplification mapping has been implemented in the present study, allowing the 8p22-23 amplicon to be narrowed from 12 cM to a <2-cM minimal amplified area located between markers D8S552 and D8 S1759, The CTSB gene maps within this region. To identify other cancer-rela ted candidate gems in this region, a positional candidate gene approach was subsequently applied to characterize this minimal critical region. An expr essed sequence tag (EST), which was included in the minimal critical region , demonstrated both amplification and overexpression, This EST and the exte nded sequence from the EST were determined to be a novel sequence in the 3' untranslated region of the human GATA-4 gene. GATA-4, a member of a zinc f inger transcription factor family, was confirmed to be amplified and overex pressed in esophageal adenocarcinomas and was localized within <0.5 kb from CTSB, Furthermore, amplification of 8p22-23 was detected in one of eight g astric cardia adenocarcinomas but was not observed in either human lung ade nocarcinomas (n = 39) or in esophageal squamous cell carcinomas (n = 24), T he relatively high frequency of the 8p22-23 amplification in esophageal (13 .6%) and gastric cardia (12.5%) adenocarcinomas may indicate a specificity of this amplicon for tumors of gastroesophageal origin.