The WT1 gene located at chromosome 11p13 codes for a transcription factor, a DNA-binding nucleoprotein, 52-62 kDa, that plays a role primarily in the development of genitourinary organs. There are at least eight isoforms ranging between 52 and 62 kDa produced by a combination of alternative splicing and RNA editing. WT1 is synthesized and reside in the cytoplasm in an inactive form. When activated through phosphorylation it is translocated to the nucleus. WT1 influences cell proliferation by suppressing bcl-2 and regulating cadherin and p53. In normal epithelia, nuclear WT1 expression is largely restricted to ovary (surface epithelium and inclusion cysts) and fallopian tube, while WT1 is not found in endometrial or cervical epithelium. As regards nonepithelial cells, nuclear WT1 is found in mesothelium and some submesothelial stromal cells, stromal cells of the female genital tract, testicular non-germinal cells, and kidney (podocytes), CD34+ bone marrow stem cells, and some splenic cells. Cytoplasmic staining, which is seen in may cell types, is probably due to Ab cross reaction with an unrelated epitope.
Although originally identified as a tumour suppressor gene, a variety neoplasms are associated with WT1 over expression. Over expression of both wild-type and mutant WT1 has been reported. Some cases show WT1 gene mutation which lead to loss of its suppressor activity. In other cases it appears that wild-type WT1 is accumulated due to mutations in downstream pathways. Among epithelial tumours, nuclear WT1 is strongly expressed in ovarian serous carcinoma (97% of the tumours, usually a widespread reaction), peritoneal serous carcinoma, ovarian transitional carcinoma, and about half of ovarian endometrioid carcinoma (grade 2 and 3 but not grade 1). Also metanephric adenoma is positive. Limited nuclear WT1 expression has been documented in a small percentage of various others carcinomas such as ovarian clear cell carcinoma, uterine papillary serous carcinoma, uterine endometrioid carcinoma, renal cell carcinoma (chromophobic and papillary), breast carcinoma, lung carcinoma, and pancreaticobiliary carcinoma. Among nonepithelial tumours, nuclear WT1 is strongly expressed in the large majority of malignant mesothelioma and sex cord-stromal tumours. Nuclear WT1 has moreover been demonstrated in Wilms' tumour (about 50% of the cases, involving epithelial, stromal and blastemal elements), malignant rhabdoid tumour, adenomatoid tumour, endometrial stromal sarcoma, uterine leiomyosarcoma, mixed mullerian tumour, as well as in some malignant lymphomas (lymphoblastic and Burkitt's lymphoma), and most cases of acute leukaemia. In desmoplastic small round cell tumour (DSRCT), nuclear WT1 is expressed in the large majority of cases due to a specific chromosomal abnormality, t(11;22)(p13;q12) that fuses EWS with WT1 leading to high production of a chimeric protein with transcriptional regulatory activity. In the chimeric protein only the C-terminus of WT1 can be detected immunohistochemically, using the mAb clone C19, while the N-terminus of WT1 cannot be detected, which means that e.g., mAb clone 6F-H2 will not give any staining reaction. In rhabdomyosarcoma, rhabdomyoblastic differentiation in Wilms' tumour, and neuroblastoma, a cytoplasmic (but not nuclear) staining for WT1 may be seen. WT1 is not demonstrated in Ewing's sarcoma/peripheral primitive neuroectodermal tumour.