Wilm's tumour gene, WT1

The WT1 protein is encoded by the WT1 gene located on chromosome 11p1315 and has four protein isoforms27. It encodes a 4 zinc finger protein that binds to the same DNA sequences as does ERG-111. While ERG-1 activates transcription, WT1 suppresses transcription. The suppressor function is lost in mutations that affect the zinc finger region11. Candidate target genes for WT-1 include e-cadherin and bcl-2, and there is interaction with p5321.

Germline deletion of one WT-1 allele, along with the neighbouring PAX6 gene, occur in the WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation)19. In the Denys-Drash syndrome, there is a missense mutation effecting zinc finger 3 or a or truncating mutation, resulting in Wilms tumour, nephropathy and genital malformation, but with partial penetrance19. A homozygous knockout mouse model fails to develop kidneys or gonads and has small heart and lungs with a incomplete diaphragm19.

Alternative RNA splicing results at least twenty four isoforms22 of WT1 with variation in the carboxy-end zinc finger region. Of two major isoforms, the -KTS form appears to mediate transcriptional activation of genes, while the +KTS form may be involved in mRNA processing23. This variety of isoforms might theoretically influence immunoreactivity of the polyclonal antibody C-19, which is directed at the carboxyl end. The monoclonal 6F-H2 is directed at the amino terminus13. The 6F-H2 antibody is reported to produce stronger homogeneous reactivity than the C-19 clone in serous ovarian tumours13, but to produce no immunoreactivity in desmoplastic small round cell tumours1.

Although WT-1 is expressed in Wilms tumour, only 10% of sporadic cases show WT-1 mutations19. There is commonly loss of heterozygocity in ovarian tumours21.

Immunohistochemical expression

The informative immunoreactivity is nuclear.







16/1710, 38/4115, 29/3013, 25/2516, 9/917, 36/3818, 14/1618, positive14, 24/2821

mixed serous/endometrioid

2/210, 2/217


1/110, 0/1516, 1/517, 0/3818, negative14, 0/1121, 2/1824


0/1215, 0/1516, 0/117, ?14, 0/1121

Brenner tumour, benign


Brenner tumour, malignant


clear cell

0/210, 0/1516, 1/417, ?14, 4/1821, 0/1124

small cell carcinoma of pulmonary type


small cell carcinoma of hypercalcaemia type

14/1530, 6/732

Fallopian tube

primary serous carcinoma

13/1316, 12/1221

primary endometrioid carcinoma


Peritoneum, primary serous carcinoma

3/316, 6/618, 19/2021


2/2910, 0/256, 6/2120



0/1813, 0/516, 5/2518, 10/1621


0/210, 0/718, 0/3521

clear cell


Cervical small cell carcinoma


Transitional cell carcinoma of bladder


Lung, adenocarcinoma

0/3310, 0/406

Lung, small cell carcinoma


Oesophagus, adenocarcinoma


Gallbladder, adenocarcinoma


Stomach, adenocarcinoma


Colon, adenocarcinoma


Pancreaticobiliary, adenocarcinoma

0/210, 0/6415

Kidney, adenocarcinoma


Prostate, adenocarcinoma

0/210, 0/106

Thyroid, adenocarcinoma



Where there is both peritoneal serous carcinoma and serous carcinoma within an endometrial polyp, they are concordantly negative for WT-1, suggesting that the peritoneal tumour is metastatic from the endometrial primary27:


Ovarian serous carcinoma



Primary peritoneal serous carcinoma


Primary uterine serous carcinoma


Peritoneal serous carcinoma with serous carcinoma in a uterine polyp



It is NOT expressed by:


Diagnostic utility




Amin 19953 (monoclonal antibody, non-commercial)



Kumar-Singh 19974 (monoclonal antibody, non-commercial)



Oates 20005 (polyclonal antibody, Santa Cruz)



Ordonez 20006 (polyclonal antibody, Santa Cruz)



Foster 20017 (polyclonal antibody, Santa Cruz)



Miettinen 20018 (polyclonal antibody, Santa Cruz)

not studied


Ordonez 20039 (monoclonal antibody, Dako 6F-H2)



 Pan 200325 (polyclonal Santa Cruz)



Chu 200526 (monoclonal antibody, Dako 6F-H2)




4% (15/348, excluding ovarian tumours)

76% (238/314)

A systematic review of eight studies (consisting of 264 epithelioid mesotheliomas and 213 pulmonary adenocarcinomas) reported sensitivities and specificities of WT-1 for epithelioid mesothelioma of 77% and 96%31.

Further studies are needed to see whether the high rate of positivity in epithelioid mesothelioma obtained by Ordonez9 using a newly available monoclonal antibody can be reproduced. Note that WT1 is commonly expressed by serous carcinomas of the ovary6.




13/13 positive, using C-191

0/11 positive1



1 Hill AD et al. WT1 staining reliably differentiates desmoplastic small round cell tumor from Ewing sarcoma/primitive neuroectodermal tumor. An immunohistochemical and molecular diagnostic study. Am J Clin Pathol 2000;114:345-353.

2 Roberts, F., McCall, A. E., Burnett, R. A. Malignant mesothelioma: a comparison of biopsy and postmortem material by light microscopy and immunohistochemistry. J Clin Pathol 2001;54:766-70.

3 Amin, K. M., L. A. Litzky, et al. (1995). "Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma." Am J Pathol 146(2): 344-56.

4 Kumar-Singh, S., K. Segers, et al. (1997). "WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis." J Pathol 181(1): 67-74.

5 Oates, J. and C. Edwards (2000). "HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma." Histopathology 36(4): 341-7.

6 Ordonez, N. G. (2000). "Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma." Am J Surg Pathol 24(4): 598-606.

7 Foster, M. R., J. E. Johnson, et al. (2001). "Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas." Arch Pathol Lab Med 125(10): 1316-20.

8 Miettinen, M., J. Limon, et al. (2001). "Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma." Am J Surg Pathol 25(5): 610-7.

9 Ordonez, N. G. (2003). "The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma." Am J Surg Pathol 27(8): 1031-51.

10 Lee, B. H., J. L. Hecht, et al. (2002). "WT1, estrogen receptor, and progesterone receptor as markers for breast or ovarian primary sites in metastatic adenocarcinoma to body fluids." Am J Clin Pathol 117(5): 745-50.

11 Rauscher, F. J., 3rd, J. F. Morris, et al. (1990). "Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence." Science 250(4985): 1259-62.

12 Lae, M. E., P. C. Roche, et al. (2002). "Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors." Am J Surg Pathol 26(7): 823-35.

13 Goldstein, N. S. and A. Uzieblo (2002). "WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas." Am J Clin Pathol 117(4): 541-5.

14 Shimizu, M., T. Toki, et al. (2000). "Immunohistochemical detection of the Wilms' tumor gene (WT1) in epithelial ovarian tumors." Int J Gynecol Pathol 19(2): 158-63.

15 Goldstein, N. S., D. Bassi, et al. (2001). "WT1 is an integral component of an antibody panel to distinguish pancreaticobiliary and some ovarian epithelial neoplasms." Am J Clin Pathol 116(2): 246-52.

16 Hashi, A., T. Yuminamochi, et al. (2003). "Wilms tumor gene immunoreactivity in primary serous carcinomas of the fallopian tube, ovary, endometrium, and peritoneum." Int J Gynecol Pathol 22(4): 374-7.

17 Logani, S., E. Oliva, et al. (2003). "Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers: histogenetic and diagnostic implications." Am J Surg Pathol 27(11): 1434-41.

18 Al-Hussaini, M., A. Stockman, et al. (2004). "WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma." Histopathology 44(2): 109-15.

19 Pritchard-Jones, K. and L. King-Underwood (1997). "The Wilms tumour gene WT1 in leukaemia." Leuk Lymphoma 27(3-4): 207-20.

20 Silberstein, G. B., K. Van Horn, et al. (1997). "Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer." Proc Natl Acad Sci U S A 94(15): 8132-7.

21 Acs, G., T. Pasha, et al. (2004). "WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium." Int J Gynecol Pathol 23(2): 110-8.

22 Scharnhorst, V., A. J. van der Eb, et al. (2001). "WT1 proteins: functions in growth and differentiation." Gene 273(2): 141-61.

23 Lee, S. B. and D. A. Haber (2001). "Wilms tumor and the WT1 gene." Exp Cell Res 264(1): 74-99. This study used clone 6F-H2.

24 Ramalingam, P., A. Malpica, et al. (2004). "The use of cytokeratin 7 and EMA in differentiating ovarian yolk sac tumors from endometrioid and clear cell carcinomas." Am J Surg Pathol 28(11): 1499-1505.

25 Pan, C. C., P. C. Chen, et al. (2003). "Expression of calretinin and other mesothelioma-related markers in thymic carcinoma and thymoma." Hum Pathol 34(11): 1155-62.

26 Chu AY, Litzky LA, Pasha TL, Acs G,Zhang PJ Utility of D2-40, a novel mesothelial marker, in the diagnosis of malignant mesothelioma. Mod Pathol 2005; 18:105-10

27 Euscher ED, Malpica A, Deavers MT, et al. Differential expression of WT-1 in serous carcinomas in the peritoneum with or without associated serous carcinoma in endometrial polyps. Am J Surg Pathol 2005; 29:1074-8

28 Gulyas M,Hjerpe A Proteoglycans and WT1 as markers for distinguishing adenocarcinoma, epithelioid mesothelioma, and benign mesothelium. J Pathol 2003; 199:479-87

29 O'Neill CJ, Deavers MT, Malpica A, et al. An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. Am J Surg Pathol 2005; 29:1034-41

30 McCluggage WG, Oliva E, Connolly LE, et al. An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 2004; 23:330-6

31 King JE, Thatcher N, Pickering CA, et al. Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data. Histopathology 2006; 48:223-32

32 Carlson JW, Nucci MR, Brodsky J, et al. Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas: the role of TTF-1, WT-1 and HPV analysis. Histopathology 2007; 51:305-12

This page last revised 30.11.2007.


©SMUHT/PW Bishop