Cadherins are a family of Ca 2+ -dependent cell-cell adhesion molecules. E-cadherin is a transmembrane protein with five tandemly repeated extracellular domains and a cytoplasmic domain that connects to the actin cytoskeleton through a complex with α-, β-and γ-catenins. E-cadherin is expressed on the cell surface in most epithelial tissues and is important for establishing cell polarity, maintaining epithelial integrity and cellular differentiation (Takeichi, 1991). The potential for E-cadherin to serve as an invasion or metastatic suppressor in epithelial tumorigenesis has been elucidated from in vitro studies. E-cadherin-negative epithelial cells grow invasive with a mesenchymal phenotype. After transfection with E-cadherin cDNA, epithelial structure is restored (Frixen et al, 1991;Vleminckx et al, 1991).Consistent with this observation is a reduced or absent E-cadherin expression in various epithelial cancers showing invasive growth (Gabbert et al, 1996;Kuczyk et al, 1998;Sulzer et al, 1998). Decreased expression of E-cadherin in Barrett's oesophagus, adenocarcinomas of the oesophagus and gastrooesophageal junction was found to be related with progression of Barrett's oesophagus to adenocarcinoma, tumour stage and lymph node metastasis (Bongiorno et al, 1995;Bailey et al, 1998). Furthermore, E-cadherin expression was an independent variable predicting survival in patients after resection for adenocarcinomas of the oesophagus (Krishnadath et al, 1997).Loss of E-cadherin expression resulted in the transition from well-differentiated adenoma to invasive carcinoma in mouse pancreatic β-cell carcinogenesis (Perl et al, 1998). Inactivating mutations in the E-cadherin gene have been described for various tumours such as lobular breast cancer (in situ) and diffuse infiltrating gastric cancer concomitant with loss of heterozygosity (LOH) at the E-cadherin locus in E-cadherin-negative tumours (Becker and Hofler, 1995;Berx et al, 1995Berx et al, , 1996Vos et al, 1997). Moreover, two recent studies showed that germline mutations in the E-cadherin gene are associated with early onset familial gastric cancer (Gayther et al, 1998;Guilford et al, 1998). Whether genetic alterations in the E-cadherin gene play a role in the pathogenesis of adenocarcinomas of the oesophagus and gastro-oesophageal junction is not known. Therefore, we screened adenocarcinomas of the oesophagus and gastro-oesophageal junction for E-cadherin gene mutations and LOH.
METHODS
Tumour specimensFresh samples of adenocarcinomas of the distal oesophagus or gastro-oesophageal junction were obtained from 45 resection specimens. For analysis the tumour samples were microdissected to enrich for cancer cells (> 75%). Nineteen tumours showed microscopic evidence of surrounding intestinal metaplasia indicative for Barrett's carcinomas. Samples of tumour and normal gastric epithelium or squamous epithelium of the oesophagus were snap-frozen and stored in liquid nitrogen. Four lymph nodes infiltrated by tumour were frozen as well. Summary Reduced expression of E-ca...