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Wilms tumor (WT) is the most frequent renal neoplasm of childhood; a myogenic component is observed in 5% to 10% of tumors. We demonstrate for the first time that myogenic WTs are associated with expression of PAX3, a transcription factor known to specify myoblast cell fate during muscle development. In a panel of 20 WTs, PAX3 was identified in 13 of 13 tumor samples with myogenic histopathology but was absent in 7 of 7 tumors lacking a myogenic component. Furthermore, we show that PAX3 is expressed in the metanephric mesenchyme and stromal compartment of developing mouse kidney. Modulation of endogenous PAX3 expression in human embryonic kidney (HEK293) cells influenced cell migration in in vitro assays. Mutations of WT1 were consistently associated with PAX3 expression in WTs, and modulation of WT1 expression in HEK293 cells was inversely correlated with the level of endogenous PAX3 protein. We demonstrate abundant PAX3 and absence of PAX2 expression in a novel cell line (WitP3) isolated from the stromal portion of a WT bearing a homozygous deletion of the WT1 gene. We hypothesize that PAX3 sets stromal cell fate in developing kidney but is normally suppressed by WT1 during the mesenchyme-to-epithelium transition leading to nephrogenesis. Loss of WT1 permits aberrant PAX3 expression in a subset of WTs with myogenic phenotype.

Beckwith-Wiedemann syndrome (BWS) patients with chromosome 11p15.5 uniparental isodisomy (UPD) have an increased risk for developing embryonal tumors. UPD in these patients involves maternal loss of heterozygosity (LOH) and paternal duplication, which leads to tissue overgrowth and tumor development. Although 11p15.5 UPD predisposes to tumorigenesis, the events leading to tumorigenesis in UPD patients remains unknown. We have examined two hepatoblastomas in the BWS patients with UPD to determine the sequence of genetic events. Constitutional 11p15.5 LOH was detected in the blood or nonneoplastic liver of the BWS patients with hepatoblastoma. Mutation of β-catenin gene (CTNNB1) was found in one hepatoblastoma. Although mutations in CTNNB1 were not found in the second hepatoblastoma, nuclear accumulation of β-catenin was detected. However, mutation of CTNNB1 or nuclear accumulation of β-catenin was not detected in the tissue with hepatomegaly which contains UPD cells. These data indicate that Wnt signal activation can be involved as a later event in BWS-associated hepatoblastoma involving 11p15.5 UPD.