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Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear ß-catenin expression, pointing to activated T-cell factor (TCF)/ß-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear ß-catenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/ß-catenin activation is caused by mutations in either adenomatous polyposis coli (APC), ß-catenin exon 3, AXIN1, AXIN2 or ß-transducin repeat-containing protein (ß-TrCP). In GEJ adenocarcinomas, very few APC and ß-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear ß-catenin expression (without ß-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear ß-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear ß-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear ß-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.British Journal of Cancer (2004) 90, 892-899. doi:10.1038/sj.bjc.6601589 www.bjcancer.com [ABSTRACT FROM AUTHOR]

In response to DNA damage, the cell cycle checkpoint kinase 2 (CHEK2) may phosphorylate p53, Cdc25A and Cdc25C, and regulate BRCA1 function, leading to cell cycle arrest and DNA repair. The truncating germline mutation CHEK2*1100delC abrogates kinase activity and confers low-penetrance susceptibility to breast cancer. We found CHEK2*1100delC in 0.5% of 190 oesophageal squamous cell carcinomas and in 1.5% of 196 oesophageal adenocarcinomas. In addition, we observed the mutation in 3.0% of 99 Barrett's metaplasias and 1.5% of 66 dysplastic Barrett's epithelia, both known precursor lesions of oesophageal adenocarcinoma. Since CHEK2*1100delC mutation frequencies did not significantly differ among oesophageal squamous cell carcinomas, adenocarcinomas and (dysplastic) Barrett's epithelia, as compared to healthy individuals, we conclude that the CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis.British Journal of Cancer (2004) 90, 888-891. doi:10.1038/sj.bjc.6601551 www.bjcancer.com [ABSTRACT FROM AUTHOR]

In two recently described human oesophageal adenocarcinoma cell lines JROECL 47 and JROECL 50, derived from one tumour, we detected identical E-cadherin and β-catenin gene mutations as in colon carcinoma cell line HCT 116. We demonstrate by HLA-typing, mutation analysis and microsatellite analysis that cell lines JROECL 47 and JROECL 50 are admixtures of the human colon adenocarcinoma cell line HCT 116. [ABSTRACT FROM AUTHOR]