WT1

Revision as of 03:02, 13 August 2018 by Paul.Defazio (talk | contribs) (→‎Other Cancers)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

Wilms Tumor 1, Wilms Tumor Protein

Genomic Location

Cytoband: 11p13

Genomic Coordinates:

chr11:32,409,321-32,457,176 [hg19]

chr11:32,387,775-32,435,630 [hg38]

Cancer Category/Type

  • Wilms’ Tumor
  • Acute Myeloid Leukaemia (AML)

Gene Overview

Structure and Function

Wilms’ Tumor 1 (WT1) was originally cloned in 1990 as a tumour suppressor gene in Wilms’ tumor, a typically pediatric renal tumor (Call et al., 1990). A combination of alternative transcription and translation start sites, splicing, and RNA editing means that WT1 has many isoforms. Human WT1 spans up to 10 exons across multiple isoforms.

All WT1 isoforms contain four zinc finger regions at the C-terminus of the protein which are involved in DNA binding (Haber et al., 1991). The N-terminal region is comprised of proline-glutamine-rich sequences and is involved in RNA and protein interactions. A nine nucleotide (three amino acid – lysine, threonine, serine, or KTS) sequence exists at the 3’ end of exon 9. Alternative splicing leads to certain isoforms retaining or omitting the KTS sequence (Haber et al., 1991). Both +KTS and -KTS isoforms appear to have non-overlapping functions and are expressed in a specific ratio in normal cells (Haber et al., 1991; Hammes et al., 2001). Germline splice-site mutations resulting in reduced +KTS/-KTS ratios are responsible for Frasier syndrome (Barbaux et al., 1997). Alternative splicing of WT1 exon 5 also leads to some isoforms containing a 17 amino acid domain responsible for transcriptional activation through interaction with the prostate apoptosis response factor PAWR (PAR4) (Richard et al., 2001).

WT1 is involved in cell growth and development. It has roles in, among others, the mesenchymal-to-epithelial transition during kidney and gonad development, the epithelial-to-mesenchymal transition during heart and diaphragm development, sensory neuron differentiation within the central nervous system, and adult tissue homeostasis (reviewed in (Hastie, 2017)). In the developing embryo it is expressed highly in the urogenital system, but in adults it can be found additionally in the central nervous system and in haematopoietic tissues (Menke et al., 1998). In vitro evidence suggests WT1 regulates BCL2 and MYC expression, and interacts with TP53 (Hewitt et al., 1995; Maheswaran et al., 1993).

Other than the tumours for which the gene is named, germline mutations affecting WT1 also variously cause WAGR syndrome (Wilms’ tumour, aniridia, genitourinary anomalies and retardation) (Riccardi et al., 1978), Denys-Drash syndrome (DDS) (Pelletier et al., 1991), the previously mentioned Frasier syndrome, and less clearly Meacham syndrome (Suri et al., 2007).

Role in Cancer

Due to the various and non-overlapping roles of WT1 depending on isoform, expression domain, and stage of development, mutations have diverse effects. WT1 can function as a tumour suppressor (as in Wilms’ Tumour) or as an oncogene (reviewed in (Yang et al., 2007)). Overexpression of WT1 is seen in a number of cancer contexts (Dohi et al., 2009; Hylander et al., 2006; Mikami et al., 2013; Rauscher et al., 2014; Ujj et al., 2016).

Wilms' Tumor

Accounting for 95% of pediatric renal tumors but rare in adults, Wilms’ tumour appears in both sporadic and hereditary forms. The tumor forms from undifferentiated cells and can be caused by multiple developmental errors. Mutations in WT1 were the first to be described (Huff and Saunders, 1993), and occur in ~15% of sporadic Wilms’ tumours (Gessler et al., 1994). In this context WT1 functions as a tumour suppressor. WT1 mutations in Wilms’ tumour are often associated with activating mutations in β-Catenin (CTNNB1) (Breslow et al., 2006; Maiti et al., 2000). WTX (also known as AMER1 or FAM123B) is also frequently mutated in WT1-mutated Wilms’ tumour (Rivera et al., 2007).

Acute Myeloid Leukemia

WT1 mutations occur in approximately 10-20% of adult and paediatric cytogenetically normal acute myeloid leukaemia (CN-AML), and with lower frequency in most other cytogenetic subgroups (Gaidzik et al., 2009; Hollink et al., 2009; Sano et al., 2013; Virappane et al., 2008). Mutations are typically frameshifts in exon 7 which truncate the DNA-binding domain or substitutions within exon 9, although other mutations do occur. Association between WT1 mutations and FLT3-ITD, KIT, and CEBPA biallelic mutations has been observed, but data varies by study (Gaidzik et al., 2009; Hollink et al., 2009; Krauth et al., 2015; Paschka et al., 2008; Sano et al., 2013; Virappane et al., 2008). WT1 mutations appear to be rarer in DNMT3A, ASXL1, TET2, IDH1, or IDH2 mutated AML (Krauth et al., 2015). WT1 and TET2 have been shown to interact, and WT1-mutant AML has aberrant DNA methylation similar to TET2 and IDH1/2 mutants, suggesting overlapping pathways (Rampal et al., 2014).

Complex cytogenetic abnormalities also correlate with reduced WT1 mutation frequency, but there is an increased frequency of WT1 mutations in individuals with t(15;17)/PML-RARA translocations (Krauth et al., 2015). WT1 mutation frequency increases in individuals less than 60 years of age. Overall, WT1 mutation appears to be associated with a poorer prognosis at least in CN-AML (Gaidzik et al., 2009; Hollink et al., 2009; Krauth et al., 2015; Paschka et al., 2008; Sano et al., 2013; Virappane et al., 2008). One report suggests that patients with WT1 and FLT3-ITD mutations may have poorer response to standard induction therapy than patients with FLT3-ITD mutations alone (Summers et al., 2007). WT1 mutations tend to be secondary rather than initiating events in leukemogenesis, and hence may only be present in subclones (Krauth et al., 2015). WT1 vaccination is being investigated as a therapeutic method in haematological malignancies (Brayer et al., 2015; Di Stasi et al., 2015).

Other Cancers

WT1 overexpression enhances ovarian cancer cell proliferation in vitro (Liu et al., 2014). Higher expression of WT1 is associated with higher stage in ovarian cancer and more aggressive clinical features, but evidence for the use of WT1 expression as a prognostic marker for overall survival is mixed (Köbel et al., 2008; Liu et al., 2014; Netinatsunthorn et al., 2006). A meta-analysis of solid cancers including breast cancer, endometrial cancer, colorectal cancer, and glioma among others found that WT1 expression correlated with worse clinical outcomes such as overall and disease-free survival (Qi et al., 2015). WT1-targeting therapies are being explored (Koido et al., 2014; Sawada et al., 2016; Shirakata et al., 2012).

Common Alteration Types

The most common WT1 alterations are missense mutations in and around residue Arg394 (NM_024426.2) or nonsense mutations which truncate some or all of the C-terminal zinc finger DNA-binding domains, but a spectrum of genetic aberrations can be observed (source: COSMIC, https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=WT1, retrieved 2018-08-13).

Copy Number Loss Copy Number Gain LOH Loss-of-Function Mutation Gain-of-Function Mutation Translocation/Fusion
EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X EXAMPLE: X

Internal Pages

Put your text here

EXAMPLE Germline Cancer Predisposition Genes

External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

EXAMPLES

WT1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

WT1 by COSMIC - sequence information, expression, catalogue of mutations

WT1 by CIViC - general knowledge and evidence-based variant specific information

WT1 by St. Jude ProteinPaint mutational landscape and matched expression data.

WT1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

WT1 by Cancer Index - gene, pathway, publication information matched to cancer type

WT1 by OncoKB - mutational landscape, mutation effect, variant classification

WT1 by My Cancer Genome - brief gene overview

WT1 by UniProt - protein and molecular structure and function

WT1 by Pfam - gene and protein structure and function information

WT1 by GeneCards - general gene information and summaries

GeneReviews - information on Wilms Tumor predisposition

References

  • Barbaux, S., Niaudet, P., Gubler, M.C., Grünfeld, J.P., Jaubert, F., Kuttenn, F., Fékété, C.N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., et al. (1997). Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat. Genet. 17, 467–470. PMID: 9398852
  • Brayer, J., Lancet, J.E., Powers, J., List, A., Balducci, L., Komrokji, R., and Pinilla-Ibarz, J. (2015). WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides. Am J Hematol 90, 602–607. PMID: 25802083
  • Breslow, N.E., Beckwith, J.B., Perlman, E.J., and Reeve, A.E. (2006). Age distributions, birth weights, nephrogenic rests, and heterogeneity in the pathogenesis of Wilms tumor. Pediatric Blood & Cancer 47, 260–267. PMID: 16700047
  • Call, K.M., Glaser, T., Ito, C.Y., Buckler, A.J., Pelletier, J., Haber, D.A., Rose, E.A., Kral, A., Yeger, H., and Lewis, W.H. (1990). Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60, 509–520. PMID: 2154335
  • Di Stasi, A., Jimenez, A.M., Minagawa, K., Al-Obaidi, M., and Rezvani, K. (2015). Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies. Front Immunol 6. PMID: 25699052
  • Dohi, S., Ohno, S., Ohno, Y., Soma, G.-I., Kyo, S., and Inoue, M. (2009). Correlation between WT1 expression and cell proliferation in endometrial cancer. Anticancer Res. 29, 4887–4891. PMID: 20032452
  • Gaidzik, V.I., Schlenk, R.F., Moschny, S., Becker, A., Bullinger, L., Corbacioglu, A., Krauter, J., Schlegelberger, B., Ganser, A., Döhner, H., et al. (2009). Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 113, 4505–4511. PMID: 19221039
  • Gessler, M., König, A., Arden, K., Grundy, P., Orkin, S., Sallan, S., Peters, C., Ruyle, S., Mandell, J., and Li, F. (1994). Infrequent mutation of the WT1 gene in 77 Wilms’ Tumors. Hum. Mutat. 3, 212–222. PMID: 8019557
  • Haber, D.A., Sohn, R.L., Buckler, A.J., Pelletier, J., Call, K.M., and Housman, D.E. (1991). Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc. Natl. Acad. Sci. U.S.A. 88, 9618–9622. PMID: 1658787
  • Hammes, A., Guo, J.K., Lutsch, G., Leheste, J.R., Landrock, D., Ziegler, U., Gubler, M.C., and Schedl, A. (2001). Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106, 319–329. PMID: 11509181
  • Hastie, N.D. (2017). Wilms’ tumour 1 (WT1) in development, homeostasis and disease. Development 144, 2862–2872. PMID: 28811308
  • Hewitt, S.M., Hamada, S., McDonnell, T.J., Rauscher, F.J., and Saunders, G.F. (1995). Regulation of the Proto-oncogenes bcl-2 and c-myc by the Wilms’ Tumor Suppressor Gene WT1. Cancer Res 55, 5386–5389. PMID: 7585606
  • Hollink, I.H.I.M., van den Heuvel-Eibrink, M.M., Zimmermann, M., Balgobind, B.V., Arentsen-Peters, S.T.C.J.M., Alders, M., Willasch, A., Kaspers, G.J.L., Trka, J., Baruchel, A., et al. (2009). Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 113, 5951–5960. PMID: 19171881
  • Huff, V., and Saunders, G.F. (1993). Wilms tumor genes. Biochim. Biophys. Acta 1155, 295–306. PMID: 8268188
  • Hylander, B., Repasky, E., Shrikant, P., Intengan, M., Beck, A., Driscoll, D., Singhal, P., Lele, S., and Odunsi, K. (2006). Expression of Wilms tumor gene (WT1) in epithelial ovarian cancer. Gynecol. Oncol. 101, 12–17. PMID: 16263157
  • Köbel, M., Kalloger, S.E., Boyd, N., McKinney, S., Mehl, E., Palmer, C., Leung, S., Bowen, N.J., Ionescu, D.N., Rajput, A., et al. (2008). Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 5, e232. PMID: 19053170
  • Koido, S., Homma, S., Okamoto, M., Takakura, K., Mori, M., Yoshizaki, S., Tsukinaga, S., Odahara, S., Koyama, S., Imazu, H., et al. (2014). Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms’ tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. Clin. Cancer Res. 20, 4228–4239. PMID: 25056373
  • Krauth, M.-T., Alpermann, T., Bacher, U., Eder, C., Dicker, F., Ulke, M., Kuznia, S., Nadarajah, N., Kern, W., Haferlach, C., et al. (2015). WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia 29, 660–667. PMID: 25110071
  • Liu, Z., Yamanouchi, K., Ohtao, T., Matsumura, S., Seino, M., Shridhar, V., Takahashi, T., Takahashi, K., and Kurachi, H. (2014). High Levels of Wilms’ Tumor 1 (WT1) Expression Were Associated with Aggressive Clinical Features in Ovarian Cancer. Anticancer Res 34, 2331–2340. PMID: 24778040
  • Maheswaran, S., Park, S., Bernard, A., Morris, J.F., Rauscher, F.J., Hill, D.E., and Haber, D.A. (1993). Physical and functional interaction between WT1 and p53 proteins. Proc. Natl. Acad. Sci. U.S.A. 90, 5100–5104. PMID: 8389468
  • Maiti, S., Alam, R., Amos, C.I., and Huff, V. (2000). Frequent Association of β-Catenin and WT1 Mutations in Wilms Tumors. Cancer Res 60, 6288–6292. PMID: 11103785
  • Menke, A.L., van der Eb, A.J., and Jochemsen, A.G. (1998). The Wilms’ tumor 1 gene: oncogene or tumor suppressor gene? Int. Rev. Cytol. 181, 151–212. PMID: 9522457
  • Mikami, T., Hada, T., Chosa, N., Ishisaki, A., Mizuki, H., and Takeda, Y. (2013). Expression of Wilms’ tumor 1 (WT1) in oral squamous cell carcinoma. J. Oral Pathol. Med. 42, 133–139. PMID: 22672247
  • Netinatsunthorn, W., Hanprasertpong, J., Dechsukhum, C., Leetanaporn, R., and Geater, A. (2006). WT1 gene expression as a prognostic marker in advanced serous epithelial ovarian carcinoma: an immunohistochemical study. BMC Cancer 6, 90. PMID: 16606472
  • Paschka, P., Marcucci, G., Ruppert, A.S., Whitman, S.P., Mrózek, K., Maharry, K., Langer, C., Baldus, C.D., Zhao, W., Powell, B.L., et al. (2008). Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J. Clin. Oncol. 26, 4595–4602. PMID: 18559874
  • Pelletier, J., Bruening, W., Kashtan, C.E., Mauer, S.M., Manivel, J.C., Striegel, J.E., Houghton, D.C., Junien, C., Habib, R., and Fouser, L. (1991). Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67, 437–447. PMID: 1655284
  • Qi, X., Zhang, F., Wu, H., Liu, J., Zong, B., Xu, C., and Jiang, J. (2015). Wilms’ tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis. Sci Rep 5. PMID: 25748047
  • Rampal, R., Alkalin, A., Madzo, J., Vasanthakumar, A., Pronier, E., Patel, J., Li, Y., Ahn, J., Abdel-Wahab, O., Shih, A., et al. (2014). DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia. Cell Reports 9, 1841–1855. PMID: 25482556
  • Rauscher, J., Beschorner, R., Gierke, M., Bisdas, S., Braun, C., Ebner, F.H., and Schittenhelm, J. (2014). WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma. J. Clin. Pathol. 67, 556–561. PMID: 24607494
  • Riccardi, V.M., Sujansky, E., Smith, A.C., and Francke, U. (1978). Chromosomal Imbalance in the Aniridia-Wilms’ Tumor Association: 11p Interstitial Deletion. Pediatrics 61, 604–610. PMID: 208044
  • Richard, D.J., Schumacher, V., Royer-Pokora, B., and Roberts, S.G.E. (2001). Par4 is a coactivator for a splice isoform–specific transcriptional activation domain in WT1. Genes Dev. 15, 328–339. PMID: 11159913
  • Rivera, M.N., Kim, W.J., Wells, J., Driscoll, D.R., Brannigan, B.W., Han, M., Kim, J.C., Feinberg, A.P., Gerald, W.L., Vargas, S.O., et al. (2007). An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315, 642–645. PMID: 17204608
  • Sano, H., Shimada, A., Tabuchi, K., Taki, T., Murata, C., Park, M., Ohki, K., Sotomatsu, M., Adachi, S., Tawa, A., et al. (2013). WT1 mutation in pediatric patients with acute myeloid leukemia: a report from the Japanese Childhood AML Cooperative Study Group. Int. J. Hematol. 98, 437–445. PMID: 23979985
  • Sawada, A., Inoue, M., Kondo, O., Yamada‐Nakata, K., Ishihara, T., Kuwae, Y., Nishikawa, M., Ammori, Y., Tsuboi, A., Oji, Y., et al. (2016). Feasibility of Cancer Immunotherapy with WT1 Peptide Vaccination for Solid and Hematological Malignancies in Children. Pediatric Blood & Cancer 63, 234–241. PMID: 26469989
  • Shirakata, T., Oka, Y., Nishida, S., Hosen, N., Tsuboi, A., Oji, Y., Murao, A., Tanaka, H., Nakatsuka, S.-I., Inohara, H., et al. (2012). WT1 peptide therapy for a patient with chemotherapy-resistant salivary gland cancer. Anticancer Res. 32, 1081–1085. PMID: 22399636
  • Summers, K., Stevens, J., Kakkas, I., Smith, M., Smith, L.L., MacDougall, F., Cavenagh, J., Bonnet, D., Young, B.D., Lister, T.A., et al. (2007). Wilms’ tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21, 550–551. PMID: 17205055
  • Suri, M., Kelehan, P., O’Neill, D., Vadeyar, S., Grant, J., Ahmed, S.F., Tolmie, J., McCann, E., Lam, W., Smith, S., et al. (2007). WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. American Journal of Medical Genetics Part A 143A, 2312–2320. PMID: 17853480
  • Ujj, Z., Buglyó, G., Udvardy, M., Beyer, D., Vargha, G., Biró, S., and Rejtő, L. (2016). WT1 Expression in Adult Acute Myeloid Leukemia: Assessing its Presence, Magnitude and Temporal Changes as Prognostic Factors. Pathol. Oncol. Res. 22, 217–221. PMID: 26531831
  • Virappane, P., Gale, R., Hills, R., Kakkas, I., Summers, K., Stevens, J., Allen, C., Green, C., Quentmeier, H., Drexler, H., et al. (2008). Mutation of the Wilms’ tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J. Clin. Oncol. 26, 5429–5435. PMID: 18591546
  • Yang, L., Han, Y., Saiz, F.S., and Minden, M.D. (2007). A tumor suppressor and oncogene: the WT1 story. Leukemia 21, 868–876. PMID: 17361230

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.