Gene Structure and Functions

The Wilms Tumour 1 ( WT1) gene is a complex gene which was originally linked to suppression of cancer in kidneys. Studies of WT1-knockout mice confirmed the important role of WT1 in the pathogenesis of Wilms’ tumour, a tumour which accounts for 95% of all childhood renal tumours. In such cases, the WT1 gene acts as a tumoursuppressor gene. Subsequent research has shown that the WT1 gene in many other cases acts as an oncogene, most prominently in leukaemia and lung cancer (even though these cancer forms can emerge as a result of many other aetiological factors). Since WT1 acts as an oncogene in many different organs, it is of great importance to evaluate how and when the WT1 gene and protein act. This information can then be used to develop immunotherapy to stabilize and treat different malignant diseases. Both phase I and phase II studies have been carried out on candidate vaccines with varying but overall promising results. The immune response does not always correlate with the clinical response, however, and the efficacy of the treatment is often limited. Further development is, therefore, needed to understand how vaccines can be improved, so that they, can hopefully fulfil a clinical role in the future. Wilms’ tumour is a paediatric kidney tumour which accounts for 95% of all renal tumours in young children. Its peak incidence is between two and three years of age, even though it is by no means a common tumour. Since the first cases of Wilms’ tumour were described (1), a large number of studies have been made on genetic alterations that may explain the occurrence its. Earlier results pointed at the deletion of a segment of chromosome 11p as a link to Wilms’ tumourigenesis (2). This segment, originally regarded as a pure suppressor gene, was termed WT1. Subsequently, it was found that that it is not only in humans that tumours develop due to lack or presence of WT1. An example of this is nephroblastoma (Wilms’ tumour) in pigs (3), which makes this gene of universal interest, i.e. not only in human medicine. As more data have been gathered, the WT1 gene has been ascribed different roles in carcinogenesis. Although it seems clear that WT1 really acts as a suppressor gene in Wilms’ tumourigenesis, it has been shown to act as an oncogene in other malignancies, such as leukaemia, glioblastoma and lung carcinoma. This has stimulated researchers to find a way of developing an immunological treatment, i.e. a vaccine, that can prevent patients from developing different types of tumours, for example leukaemia and lung carcinoma. A successful outcome of this struggle would lead to a completely new dimension in cancer prevention. Gene Structure and Functions The WT1 gene is a complex gene that consists of 10 exons located on human chromosome 11p13 (4). WT1 is characterized by at least 36 isoforms. All these isoforms have four Zn fingers on their C-terminus. Isoforms can occur, for example, by including or excluding the three amino acids lysine, threonine and serine (−/+KTS), which have their place between Zn fingers three and four (5). Other isoforms can originate from the use of an upstream and in-frame CTG start codon, an internal ATG start codon at the end of exon 1 and a residue in exon 6 subject to RNA editing (6). Some of the 36 isoforms have only been described in murine and human samples, whilst others can be found in all mammals. The only isoforms which can be found in all vertebrates are the KTS variants (6). The WT1 protein has many different key roles in the normal development of the genitourinary system as well as in tumourigenesis. Mutations or deletion of the WT1 gene 675 Correspondence to: Wilhelm Engström, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, PO Box 75007, Uppsala, Sweden. Tel: +46 18671193, Fax +46 18673532, e-mail: [email protected]