E-cadherin gene mutations are rare in adenocarcinomas of the oesophagus

Abstract

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...

Molecular genetic analysis of the von Hippel-Lindau and human peroxisome proliferator-activated receptor ? tumor-suppressor genes in adenocarcinomas of the gastroesophageal junction

“…18 DNA from cell lines and tissue samples was isolated according to standard procedures. 19 Microdissection was performed to ensure that the tumor tissue consisted of at least 75% tumor cells. Normal mouse DNA was used as the negative control for xenograft DNA.…”

“…19 In all tumor samples, LOH was determined with 2 microsatellite markers that map on 3p, where both genes are located. Markers D3S1110 and D3S1317 were tested on tumor and normal DNA in a radioactive PCR, as described previously.…”

Involvement of Members of the Cadherin Superfamily in Cancer

“…Missense mutations are infrequent in these two subtypes of cancer but frequent in monophasic synovial sarcomas (Saito et al 2001). E-cadherin mutations are rare in carcinomas of bladder, colon, endometrium, lung, esophagus, ovary, and thyroid, and in intrahepatic cholangiocarcinoma (Risinger et al 1994;Soares et al 1997;Wijnhoven et al 1999;Taddei et al 2000;Endo et al 2001;VecseySemjen et al 2002).…”

Molecular Biology of Barrett’s Adenocarcinoma

“…No mutations could be detected in esophageal adenocarcinomas, despite frequent loss of heterozygosity of the E-cadherin locus at 16q22. 166 Besides establishing cell-cell adhesion, ␤-catenin was shown recently to function in cell signaling. 167,168 Under normal conditions, ␤-catenin is bound to the cytoplasmic tail of E-cadherin.…”