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

Abstract：

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

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Koppert LB,van der Velden AW,van de Wetering M,Abbou M,van den Ouweland AM,Tilanus HW,Wijnhoven BP,Dinjens WN

doi

10.1038/sj.bjc.6601589

subject

Has Abstract

pub_date

2004-02-23 00:00:00

pages

892-9

issue

eissn

0007-0920

issn

1532-1827

pii

6601589

journal_volume

pub_type

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