WNT/beta-catenin pathway activation in Wilms tumors: a unifying mechanism with multiple entries?
Based on characterization of both genomic and expression status of WT1 and CTNNB1 (beta-catenin) in a series of 60 Wilms tumor samples, combined with genome-wide expression profiling of these tumors, normal mature and fetal kidney controls, we show that WT1/beta-catenin expression was a better classifier than WT1/CTNNB1 mutations. We present molecular data supporting that the WNT pathway is involved in both tumor classes, with and without WT1/beta-catenin alterations. In the tumor class with WT1/beta-catenin alterations, we identified overexpression of 14 previously unreported WNT target genes, including TWIST1. We show that the TWIST1 protein was specifically expressed in these tumors, where staining was restricted to the stromal, nuclear beta-catenin positive, component. By comparing the state of the WNT pathway in tumors without WT1/beta-catenin alterations and fetal kidneys we provide evidence that suggests that these tumors have a heightened level of pathway activation. We characterized mutations of the WNT pathway regulator gene WTX in 16% of this tumor class. Moreover, genome-transcriptome correlation analysis allowed us to identify three other WNT pathway regulator genes that could participate in the activation of the WNT pathway: BCL9 (1p36.2), CTNNBIP1 (1p36.2), and CBY1 (22q13.1). These genes thus represent new potential important actors in WT tumorigenesis.
Corbin
Marie
M
Inserm, U574, Hôpital Necker-Enfants Malades, Paris, France.
de Reyniès
Aurélien
A
Rickman
David S
DS
Berrebi
Dominique
D
Boccon-Gibod
Liliane
L
Cohen-Gogo
Sarah
S
Fabre
Monique
M
Jaubert
Francis
F
Faussillon
Marine
M
Yilmaz
Funda
F
Sarnacki
Sabine
S
Landman-Parker
Judith
J
Patte
Catherine
C
Schleiermacher
Gudrun
G
Antignac
Corinne
C
Jeanpierre
Cécile
C
D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / 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*
C495270:CTNNB1 protein, human; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D025721:WT1 Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D053612:Janus Kinases