jeudi 15 décembre 2011

Mutated genes in cancer (37) – WT1


In databases:

● Ensembl ( ENSG00000184937
● UniProt ( P19544
● OMIM (  607102
● GeneCards ( WT1
● HGNC ( 12796 or WT1

Gene locus :


Protein name:

Wilms tumor 1

Protein Size:

449 amino acids; about 49 kDa


This gene encodes a transcription factor that plays an important role in cellular development and cell survival. It has an essential role in the normal development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. It is highly expressed in the developing kidney.

Cancer-related alterations

Various types of germline mutations have been observed, mostly affecting zinc fingers in exons 7-10.

Genetic WT1 alterations may be the cause of Wilms tumor (WT), WAGR syndrome, Frasier syndrome (FS), Denys-Drash syndrome (DDS), desmoplastic small round cell tumor (DSRCT).

WT is an embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms.

WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), aniridia (absence of the coloured part of the eye, the iris), genitourinary anomalies (gonadoblastoma), and mental retardation. WAGR syndrome is caused by a mutation on chromosome 11 in the 11p13 region. Specifically, several genes in this area are deleted, including the PAX6 ocular development gene and the Wilms' tumour gene (WT1).

FS is characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant.

DDS is a typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic.

In DSRCT, a t(11;22)(p13;q12) translocation leads to an in frame fusion of EWSR1 exons 1-7 and WT1 exons 8-10, and to an abnormal EWSR1-WT1 protein.

Somatic alterations: biallelic WT1 inactivation has been found in Wilms' tumors (<15%) and some mesotheliomas and granulosa cell tumors. Somatic WT1 alterations have been observed in kidney and in haematopoietic and lymphoid tissue (myelodysplastic syndrome in progression and in acute leukemia). They are insertion or substitutions and are frequent in a gene region corresponding to amino acids 300-316.


Immunotherapy: hundreds of cancer antigens have been identified, one of which is the WT1, which has two features appropriate for a cancer antigen. First, WT1 gene possesses oncogenic functions. This is a theoretical advantage for using its product, the WT1 protein, as a target antigen, because WT1 expression is thought to be essential for maintaining the transformed characteristics of cancer cells, and tumor escape from immune surveillance as a result of its downmodulation is unlikely to occur. Second, wild-type WT1 is expressed in many kinds of haematological and solid malignancies, which indicates that WT1-targeting immunotherapy can be used for a variety of malignancies (Oka Y & Sugiyama H. 2010).

References (open access):

WT1 (Wilms' tumor gene 1): biology and cancer immunotherapy. Sugiyama H. Jpn J Clin Oncol. 2010 May;40(5):377-87.

WT1 peptide vaccine, one of the most promising cancer vaccines: its present status and the future prospects. Oka Y, Sugiyama H. Immunotherapy. 2010 Sep;2(5):591-4.

Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909. Kuball J, de Boer K, Wagner E, Wattad M, Antunes E, Weeratna RD, Vicari AP, Lotz C, van Dorp S, Hol S, Greenberg PD, Heit W, Davis HL, Theobald M. Cancer Immunol Immunother. 2011 Feb;60(2):161-71.

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