Wilms' tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis

Qi, Xiaowei; Zhang, Fan; Wu, Hong; Liu, Junlan; Zong, Beige; Xu, Chuan; Jiang, Jun

doi:10.1038/srep08924

Cited by 85 publications

(60 citation statements)

References 58 publications

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“…This enrichment indicates that WT1 has the ability to influence many of the properties of malignancy through transcriptional regulation of target genes, consistent with the well-documented role for WT1 in tumor development. 2,32,34 Another interesting group is nucleocytoplasmic transport. Accumulating evidence suggests that transport from the nucleus to cytoplasm is tightly regulated and at least in some instances selective for certain transcripts, 35 potentially providing WT1 with further possibilities to influence protein production.…”

Section: Wt1 Binds To Genes Related To Development and Oncogenic Procmentioning

confidence: 99%

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

et al. 2016

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T he zinc finger transcription factor Wilms tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (±KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of the WT1 -KTS isoform at the expense of the WT1 +KTS isoform is associated with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with the involvement of WT1 in acute myeloid leukemia.

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Section: Wt1 Binds To Genes Related To Development and Oncogenic Procmentioning

confidence: 99%

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

et al. 2016

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“…WT4869 is a novel peptide derived from the tumor-associated antigen Wilms' tumor gene 1 (WT1), which is commonly overexpressed in leukemias, MDS (7) and a variety of solid tumors. (8) WT1 is ranked the most useful among 75 cancer antigens by the National Institutes of Health, and is attracting attention as a peptide suited for use as a cancer vaccine. (9) The WT1 235-243 peptide derived from the WT1 gene product is restricted to the human leukocyte antigen (HLA)-A*24:02 that is present in approximately 60% of the Japanese population.…”

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confidence: 99%

Phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with myelodysplastic syndrome

et al. 2017

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WT4869 is a synthetic peptide vaccine derived from the Wilms’ tumor gene 1 (WT1) protein. This phase 1/2 open‐label study evaluated the safety and efficacy of WT4869, and biomarkers for response, in patients with myelodysplastic syndrome. WT4869 (5–1200 μg/dose) was administered intradermally every 2 weeks, according to a 3 + 3 dose‐escalation method in higher‐risk (International Prognostic Scoring System score ≥1.5) or lower‐risk (score <1.5) red blood cell transfusion‐dependent patients with myelodysplastic syndrome. Twenty‐six patients were enrolled and treated (median age, 75 years; range, 32 to 89). The most common adverse event was injection site reaction (61.5%). Main grade 3 or 4 adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated blood creatine phosphokinase levels and hypoalbuminemia (all 7.7%). Dose‐limiting toxicities occurred in 1 patient in the 50 μg/dose cohort (pyrexia, muscle hemorrhage and hypoalbuminemia) and 1 patient in the 400 μg/dose cohort (pneumonitis); however, the maximum tolerated dose could not be determined from this trial. The overall response rate was 18.2%, the disease control rate was 59.1% and median overall survival was 64.71 weeks (95% confidence interval: 50.29, 142.86) as assessed by the Kaplan–Meier method. Subgroup analysis of azacitidine‐refractory patients with higher‐risk myelodysplastic syndrome (11 patients) showed median overall survival of 55.71 weeks (approximately 13 months). WT1‐specific cytotoxic T lymphocyte induction was observed in 11 of 25 evaluable patients. WT4869 was well tolerated in patients with myelodysplastic syndrome and preliminary data suggest that WT4869 is efficacious. This trial was registered at www.clinicaltrials.jp as JapicCTI‐101374.

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“…The oncogenic roles during tumorigenesis, such as promotion of growth, inhibition of differentiation, resistance to cell death, and promotion of tumor angiogenesis (8)(9)(10)20). Further, wildtype WT1 is overexpressed in various human cancers including PDAC and is a poor prognostic marker (11)(12)(13)(14). In addition to these oncogenic functions, WT1 is immunogenic.…”

Section: Introductionmentioning

confidence: 99%

Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study

Nishida

Ishikawa

Egawa

et al. 2018

Cancer Immunology Research

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Conflict of interestThe authors declare no potential conflicts of interest with respect to this manuscript. AbstractWe investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it to gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01-or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTLs). Of 91 patients enrolled, 85were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival (PFS) (hazard ratio [HR], 0.66; P = 0.084) and improved overall survival rate at 1 year (1-year OS%) (GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363).These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well-tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared to the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86) (P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses.

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Wilms' tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis

Cited by 85 publications

References 58 publications

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

Phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with myelodysplastic syndrome

Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study

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