No evidence for involvement of beta-catenin and APC in urothelial carcinomas.
The wnt pathway plays an important role in embryonal patterning and cell fate determination, involving stabilization of nuclear and cytoplasmic beta-catenin (CTNNB1) mediated by APC, axin, and other proteins. Uncomplexed beta-catenin binds to TCF/LEF transcription factors and activates the expression of growth regulatory target genes such as c-myc or cyclin D1. In colorectal and other cancers, constitutive wnt signaling results frequently from mutations in one or more pathway components, e.g. APC and beta-catenin, resulting in nuclear and/or cytoplasmic accumulation of beta-catenin. In the present study, the most frequent alterations in the CTNNB1 and APC genes were investigated in primary urothelial bladder tumors and cell lines. Snap-frozen bladder tumors (n=99) of different stages and grades and 4 cell lines (RT4, RT112, J82, UROtsa) were investigated for APC allelic deletions by loss of heterozygosity (LOH) analysis. The most frequent mutated regions of CTNNB1 (degradation box in the third exon) and APC (mutation cluster region) were directly sequenced. Beta-catenin expression was analyzed by immunofluorescence in the cell lines. LOH at the APC gene locus on chromosome 5q21 was found in 7 of 72 (10%) of the informative cases. No mutations were found in either CTNNB1 or APC. A previously described polymorphism at codon 1493 of the APC gene was detected in 8 tumors and 3 cell lines. All cell lines showed normal membranous beta-catenin staining without evidence for nuclear or cytoplasmic accumulation. Alteration of APC and beta-catenin, which are the most frequent wnt pathway alterations in many tumor types, are rare events in urothelial carcinomas. Other wnt pathway members, such as axin, may play an important role in urothelial carcinogenesis.
Stoehr
Robert
R
Institute of Pathology, University of Regensburg, 93042 Regensburg, Germany.
Krieg
Rene C
RC
Knuechel
Ruth
R
Hofstaedter
Ferdinand
F
Pilarsky
Christian
C
Zaak
Dirk
D
Schmitt
Ruediger
R
Hartmann
Arndt
A
D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis* / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002895:Chromosomes, Human, Pair 5; D003062:Codon; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D005091:Exons; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003062:Codon; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin