Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear β-catenin expression

Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear β-catenin expression, pointing to activated T-cell factor (TCF)/β-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear β-catenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/β-catenin activation is caused by mutations in either adenomatous polyposis coli (APC), β-catenin exon 3, AXIN1, AXIN2 or β-transducin repeat-containing protein (β-TrCP). In GEJ adenocarcinomas, very few APC and β-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 β-catenin expression (without β-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 β-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear β-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 β-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

Evaluation of a Finite-Element Sea-Ice ocean model (FESOM) setup to study the interannual to decadal variability in the deep-water formation rates.

The characteristics of a global set-up of the Finite-Element Sea-Ice Ocean Model under forcing of the period 1958–2004 are presented. The model set-up is designed to study the variability in the deep-water mass formation areas and was therefore regionally better resolved in the deep-water formation areas in the Labrador Sea, Greenland Sea, Weddell Sea and Ross Sea. The sea-ice model reproduces realistic sea-ice distributions and variabilities in the sea-ice extent of both hemispheres as well as sea-ice transport that compares well with observational data. Based on a comparison between model and ocean weather ship data in the North Atlantic, we observe that the vertical structure is well captured in areas with a high resolution. In our model set-up, we are able to simulate decadal ocean variability including several salinity anomaly events and corresponding fingerprint in the vertical hydrography. The ocean state of the model set-up features pronounced variability in the Atlantic Meridional Overturning Circulation as well as the associated mixed layer depth pattern in the North Atlantic deep-water formation areas