The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. WT1 is required for normal formation of the genitourinary system and mesothelial tissues.

The WT1 protein is a transcriptional activator of genes involved in renal and gonadal differentiation. It regulates the mesenchymal to epithelial transition that occurs in kidney development.

Development

 splenic organogenesis
 glomerulogenesis in renal organogenesis

WT1 expression in normal cells

 WT1 expression in angiogenic tumours of the skin. (15982325)

• WT1 is an endothelial marker. (15982325)
• WT1 protein expression is maintained during angiogenesis and malignant transformation of endothelial cells.
• Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions. (16230568)

In CD34+ haematopoietic progenitors and down-regulated in more-differentiated cells, the WT1 transcription factor has been implicated in regulation of apoptosis, proliferation and differentiation.

Pathology

The WT1 gene, located on chromosome 11p13, is associated with the development of Wilms tumor, a pediatric kidney cancer. Both inherited and sporadic forms of Wilms tumor occur, and mutational inactivation of the WT-1 locus has been seen in both forms. Although not precisely known, it is likely that the tumorigenic effect of WT-1 deficiency is intimately connected with the role of the gene in the differentiation of genitourinary tissues.

 mutations in malformative syndromes

• dominant negative mutations in the Wilms tumour (WT1) gene in the Denys-Drash syndrome
• constitutional mutations in Frasier syndrome (chronic renal failure and XY gonadal dysgenesis)(MIM.136680)

 constitutional mutations in familial Wilms tumor

 constitutional WT1 mutations in nonsyndromic Wilms tumor patients (2.1%) (15483024)

• Most mutations occurred in children with unilateral WT without associated genitourinary abnormalities. (15483024)
• Two factors that may indicate that an individual is carrying a germline WT1 mutation are an early age of onset and stromal-predominant histology of the WT. (15483024)

 constitutional mutations in mesangial sclerosis
 constitutional mutations in primary steroid-resistant focal and segmental glomerulosclerosis

 mutations in sporadic tumors

• constitutional or somatic mutations in the Wilms tumor(<15% patients)
• somatic mutations in mesothelioma

 WT1 deletions

• WAGR syndrome (11p13 deletion)

 WT1 overexpression in tumors

• progression of prostate carcinomas (17137506)
• endometrial stromal sarcoma (17531467)
• uterine undifferentiated sarcomas (17531467)
• malignant glial tumors (17457020)
• myelodysplastic syndromes (17454605, 17454584)
• ovarian sertoli cell tumor (96%) (17721194)
• ovarian endometrioid borderline tumor (16%) (17721194)
• ovarian well-differentiated endometrioid carcinoma (13%) (17721194)
• ovarian sertoliform endometrioid carcinoma (25%) (17721194)
• progression of ovarian serous adenocarcinomas (OSAs) (17594113, 17540436)

Immunochemistry

 WT1 positivity of diagnostic use in

• infantile hemangiomas (16230568)
• ovarian sertoli cell tumor (17721194)

References

 van Heyningen V, Hoovers JM, de Kraker J, Crolla JA. Elevated risk of Wilms tumour in aniridia cases with submicroscopic WT1 deletion. J Med Genet. 2007 Jul 14;PMID: 17630404

 Devilard E, Bladou F, Ramuz O, Karsenty G, Dales JP, Gravis G, Nguyen C, Bertucci F, Xerri L, Birnbaum D. FGFR1 and WT1 are markers of human prostate cancer progression. BMC Cancer. 2006 Nov 30;6:272. PMID: 17137506

 Lawley LP, Cerimele F, Weiss SW, North P, Cohen C, Kozakewich HP, Mulliken JB, Arbiser JL. Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions. Arch Dermatol. 2005 Oct;141(10):1297-300. PMID: 16230568

Reviews

 Yang L, Han Y, Suarez Saiz F, Minden MD. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007 Jul;21(7):1603. PMID: 17579655

 Yang L, Han Y, Saurez Saiz F, Minden MD. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007 May;21(5):868-76. PMID: 17361230

 Ariyaratana S, Loeb DM. The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. Expert Rev Mol Med. 2007 May 24;9(14):1-17. PMID: 17524167

 Timar J, Meszaros L, Orosz Z, Albini A, Raso E. WT1 expression in angiogenic tumours of the skin. Histopathology. 2005 Jul;47(1):67-73. PMID: 15982325

 Little SE, Hanks SP, King-Underwood L, Jones C, Rapley EA, Rahman N, Pritchard-Jones K. Frequency and heritability of WT1 mutations in nonsyndromic Wilms? tumor patients: a UK Children?s Cancer Study Group Study. J Clin Oncol. 2004 Oct 15;22(20):4140-6. PMID: 15483024

 Roberts SG. Transcriptional regulation by WT1 in development. Curr Opin Genet Dev. 2005 Oct;15(5):542-7. PMID: 16099645

References

 Zhao C, Bratthauer GL, Barner R, Vang R. Diagnostic utility of WT1 immunostaining in ovarian sertoli cell tumor. Am J Surg Pathol. 2007 Sep;31(9):1378-86. PMID: 17721194

 Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V. Twenty-four new cases of WT1 germline mutations and review of the literature: Genotype/phenotype correlations for Wilms tumor development. Am J Med Genet. 2004 Jun 15;127A(3):249-57. PMID: 15150775