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Wilms' tumour: connecting tumorigenesis and organ development in the kidney

Key Points

  • Wilms' tumour is a common paediatric malignancy that is derived from pluripotent embryonic renal precursors.

  • WT1 was the first gene shown to be inactivated in Wilms' tumour and it is essential for kidney development. Wt1-knockout mice lack kidneys and WT1 has been implicated in both the survival and differentiation of cells in renal development. Germline WT1 mutations account for Wilms' tumours and urogenital abnormalities in the WAGR (Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) and Denys–Drash syndromes.

  • The two main WT1 isoforms, −KTS and +KTS, have overlapping but distinct functions in renal and gonadal development. These defects are illustrated by Frasier syndrome (lacking the +KTS form) and by mice engineered to lack specific isoforms. Kidneys are abnormal and hypoplastic in the absence of the −KTS form of WT1 whereas the absence of the +KTS form causes defects in the function of glomerular podocytes.

  • Desmoplastic small-round-cell tumour (DSRCT) is a poorly differentiated childhood malignancy in which WT1 acts as a translocation partner with the EWS gene to generate a chimaeric oncogene. Transcriptional targets of this fusion protein include PDGFA, which might contribute to the characteristic stromal reaction observed in these tumours.

  • The WNT pathway, which is critical for kidney development, has been implicated in Wilms' tumour by the identification of activating β-catenin mutations. WT1 and β-catenin mutations are frequently present in the same tumours.

  • The genetic defects that account for most cases of Wilms' tumour remain unknown. Given the intimate connection between Wilms' tumour and renal development, it is likely that novel genes implicated in Wilms' tumour will be important in both tumorigenesis and organogenesis.

Abstract

Wilms' tumour, or nephroblastoma, is a common childhood tumour that is intimately linked to early kidney development and is often associated with persistent embryonic renal tissue and other kidney abnormalities. WT1, the first gene found to be inactivated in Wilms' tumour, encodes a transcription factor that functions as both a tumour suppressor and a critical regulator of renal organogenesis. Our understanding of the roles of WT1 in tumour formation and organogenesis have advanced in parallel, providing a striking example of the intersection between tumour biology, cellular differentiation and normal organogenesis.

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Figure 1: Histological parallels between the developing kidney and Wilms' tumour.
Figure 2: Outline of kidney development.
Figure 3: Alternative splicing of WT1.
Figure 4: Expression of WT1 in the developing kidney.
Figure 5: EWSR1–WT1 translocation in desmoplastic small round cell tumour.
Figure 6: Mutations in β-catenin in Wilms' tumour result in constitutively active signalling.

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Filippo Spreafico, Conrad V. Fernandez, … Kathy Pritchard-Jones

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Acknowledgements

This work was supported by the National Cancer Institute. We thank D. Genest (Brigham and Women's Hospital, Boston, USA) and S. Vargas (Children's Hospital, Boston, USA) for their help with histological images.

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DATABASES

Entrez Gene

CDKN1C

CTNNB1

EWSR1

FWT1

GPC3

H19

IGF2

PAX6

TP53

WT1

National Cancer Institute

AML

DSRCT

Ewing sarcoma

mesothelioma

neuroblastoma

retinoblastoma

Wilms' tumour

OMIM

BWS

DDS

Frasier syndrome

SGBS

FURTHER INFORMATION

Daniel Haber's laboratory

Glossary

ANIRIDIA

Absence of the iris.

BLASTEMA

A collection of undifferentiated cells seen in the early stages of organ development.

URETERIC BUD

An outgrowth of the Wolffian duct that invades the metanephric mesenchyme at the initation of kidney organogenesis. The collecting ducts of the mature kidney are derivatives of the ureteric bud.

METANEPHRIC MESENCHYME

A collection of mesenchymal cells that will give rise to the nephrons of the kidney through mesenchymal-to-epithelial transformation.

GLOMERULUS

A tuft of capillary loops located in the beginning of a nephron. The capillaries are surrounded by a cup-like collection of glomerular podocytes (Bowman's capsule). Blood is filtered across the endothelial and epithelial cells to produce urine.

LOSS OF IMPRINTING

Imprinting affects specific chromosomal locations and is the epigenetic silencing of one allele of a gene owing to its parental origin. This silencing can be disrupted in tumours, leading to expression of both alleles and hence overexpression of a given gene.

MACROGLOSSIA

An abnormally enlarged tongue.

VISCEROMEGALY

Abnormally enlrged viscera.

POLYDACTYLY

The presence of additional fingers or toes.

LOSS OF HETEROZYGOSITY

In cells carrying a mutation in one of the two alleles of a tumour-suppressor gene, the gene can become fully inactivated by deletion or conversion of the wild-type allele into the mutant form. This change from a heterozygous to a homozygous state can be detected by appropriate genetic markers and points to the existence of tumour-suppressor genes when it occurs at a high frequency in a given location.

GLOMERULAR PODOCYTES

The highly specialized epithelial cells that surround the capillaries of the glomerulus. These cells are attached to the capillary basement membrane by foot processes separated by filtration slits and contribute to the formation of a filtration barrier.

YAC (YEAST ARTIFICIAL CHROMOSOME) RESCUE

A large genomic fragment containing a gene and its regulatory elements can be propagated in yeast and then reintroduced into a knockout mouse strain. The knockout phenotype can be partially rescued because the regulatory elements that are included will allow gene expression to closely resemble that of the wild-type transcript.

PROTEINURIA

An abnormally elevated concentration of protein in the urine. This is a sign of glomerular dysfunction.

GLOMERULAR SCLEROSIS

Scarring of the renal glomerulus. Often associated with chronic renal failure.

MYELO-MONOCYTIC DIFFERENTIATION

Differentiation of haematopoietic precursors along the monocyte pathway, one of several possible differentiation programs.

DESMOPLASIA

A stromal reaction to the presence of tumour cells characterized by fibroblast recruitment, collagen deposition and angiogenesis.

MACROSOMIA

An abnormally large body.

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Rivera, M., Haber, D. Wilms' tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 5, 699–712 (2005). https://doi.org/10.1038/nrc1696

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