Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition.
Wilms' tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649-5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF.
Li
Chi-Ming
CM
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
Guo
Meirong
M
Borczuk
Alain
A
Powell
Charles A
CA
Wei
Michelle
M
Thaker
Harshwardhan M
HM
Friedman
Richard
R
Klein
Ulf
U
Tycko
Benjamin
B
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004848:Epithelium; D051858:Forkhead Transcription Factors; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000196:embryology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008648:Mesoderm / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D019255:NADPH Oxidases; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D051762:PAX2 Transcription Factor; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; C079853:ETV4 protein, human; C090173:FOXG1 protein, human; C115810:FZD7 protein, human; D051858:Forkhead Transcription Factors; D051157:Frizzled Receptors; C484298:HOXA11 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C404944:PRAME protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C104147:SALL2 protein, human; C099236:SIX1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C022709:superoxide-forming enzyme; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases