Canonical WNT signalling determines lineage specificity in Wilms tumour.
Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of beta-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of beta-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of beta-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.
Fukuzawa
R
R
Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. ryuji.fukuzawa@otago.ac.nz
Anaka
M R
MR
Weeks
R J
RJ
Morison
I M
IM
Reeve
A E
AE
D048868:Adaptor Proteins, Signal Transducing; D002454:Cell Differentiation; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009399:Nephrons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C035170:IGF2 protein, human; D025521:Tumor Suppressor Proteins; D025721:WT1 Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II