11p13 MIM.607102 MIM.194070
Thursday 28 August 2003
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.
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.
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
- 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)
WT1 positivity of diagnostic use in
WT1, the Wilms tumor gene product, can be expressed in various tumors from different anatomic sites, including some types of ovarian tumors.
Regarding ovarian tumors, most studies have focused on surface epithelial-stromal tumors in which serous carcinomas are usually positive and endometrioid carcinomas are negative.
WT1 may be frequently expressed in sex cord-stromal tumors. As pure Sertoli cell tumor can be in the histologic differential diagnosis of endometrioid tumors (particularly borderline tumor and carcinoma) and carcinoid, immunostaining for WT1 might be of diagnostic value. Nuclear expression of WT1 is present in 96% of Sertoli cell tumors, 16% of endometrioid borderline tumors, 13% of classic well-differentiated endometrioid carcinomas, 25% of sertoliform endometrioid carcinomas, and 0% of carcinoids. In Sertoli cell tumors, expression is diffuse (>50% of positive cells) in all positive cases. When positive in the non-Sertoli cell tumors, the extent of expression tended to be focal to patchy (50% or less positive cells). WT1 is useful for the distinction of Sertoli cell tumor from endometrioid tumors and carcinoid. The diagnostic utility of WT1 in Sertoli cell tumor is similar to inhibin but better than that of calretinin. (17721194)
References - Immunochemistry
WT1 staining reliably differentiates desmoplastic small round cell tumor from Ewing sarcoma/primitive neuroectodermal tumor. An immunohistochemical and molecular diagnostic study. Hill DA, Pfeifer JD, Marley EF, Dehner LP, Humphrey PA, Zhu X, Swanson PE. Am J Clin Pathol. 2000 Sep;114(3):345-53. PMID: 10989634 [Free]
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
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
References - Clinical genetics
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
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