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Wilms tumor gene (WT1) is used as a marker for the diagnosis and prognosis of ovarian cancer. However, the molecular mechanisms involving WT1 in ovarian cancer require further study. Herein, we used bioinformatics and other methods to identify important pathways and hub genes in ovarian cancer affected by WT1. The results showed that WT1 is highly expressed in ovarian cancer and is closely related to the overall survival and progression-free survival (PFS) of ovarian cancer. In ovarian cancer cell line SKOV3, WT1 downregulation increased the mRNA expression of 638 genes and decreased the mRNA expression of 512 genes, which were enriched in the FoxO, AMPK, and the Hippo signaling pathways. The STRING online tool and Cytoscape software were used to construct a Protein-protein interaction (PPI) network and for Module analysis, and 18 differentially expressed genes (DEGs) were selected. Kaplan-Meier plotter analysis revealed that 16 of 18 genes were related to prognosis. Analysis of GEPIA datasets indicated that 7 of 16 genes were differentially expressed in ovarian cancer tissues and in normal tissues. The expression of IGFBP1 and FBN1 genes increased significantly after WT1 interference, while the expression of the SERPINA1 gene decreased significantly. The correlation between WT1 expression and that of these three genes was consistent with that of ovarian cancer tissues and normal tissues. According to the GeneMANIA online website analysis, there were complex interactions between WT1, IGFBP1, FBN1, SERPINA1, and 20 other genes. In conclusion, we have identified important signaling pathways involving WT1 that affect ovarian cancer, and distinguished three differentially expressed genes regulated by WT1 associated with the prognosis of ovarian cancer. Our findings provide evidence outlining mechanisms involving WT1 gene expression in ovarian cancer and provides a rational for novel treatment of ovarian cancer.

Background: The X‐chromosomally linked gene WTX is a human disease gene and a member of the AMER family. Mutations in WTX are found in Wilms tumor, a form of pediatric kidney cancer and in patients suffering from OSCS (Osteopathia striata with cranial sclerosis), a sclerosing bone disorder. Functional data suggest WTX to be an inhibitor of the Wnt/β‐catenin signaling pathway. Deletion of Wtx in mouse leads to perinatal death, impeding the analysis of its physiological role. Results: To gain insights into the function of Wtx in development and homeostasis we have used zebrafish as a model and performed both knockdown and knockout studies using morpholinos and transcription activator‐like effector nucleases (TALENs), respectively. Wtx knockdown led to increased Wnt activity and embryonic dorsalization. Also, wtx mutants showed a transient upregulation of Wnt target genes in the context of caudal fin regeneration. Surprisingly, however, wtx as well as wtx/amer2/amer3 triple mutants developed normally, were fertile and did not show any anomalies in organ maintenance. Conclusions: Our data show that members of the zebrafish wtx/amer gene family, while sharing a partially overlapping expression pattern do not compensate for each other. This observation demonstrates a remarkable robustness during development and regeneration in zebrafish. Key Findings: Wtx knockdown causes patterning defects in early zebrafish embryogenesis.Mutation of zebrafish wtx is not associated with an obvious embryonic phenotype.Lack of compensation among the wtx/amer gene family.Triple wtx/amer2/amer3 mutants develop normally and are fertile. [ABSTRACT FROM AUTHOR]

There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital development and mutations in this gene have been associated with DDS. DDS should be considered in the differential diagnosis of newborns with genital anomalies. In contrast to other conditions with 46,XY disorders of sex development, individuals with DDS often have duplicated genital organs (a double vagina, cervix or uterus). A double uterus has not yet been reported with 1390G>A (Arg464 Asn) mutation. However, duplicated genitals have been reported with other genetic mutations in patients with DDS. The duplicated genitals in DDS may be associated with low anti-Mullerian hormone (AMH) secretion. Measurement of the AMH levels may add to our understanding of variations in genital development and their abnormalities in disorders such as DDS. In conclusion, this is first case of low level of AMH and double uterus in 1390G>A (Arg464 Asn) mutations of DDS male.

Background: The Wilms tumor 1 (WT1) gene is originally defined as a tumor suppressor gene and a transcription factor that overexpressed in leukemic cells. It is highly expressed in more than 80% of acute myeloid leukemia (AML) patients, both in bone marrow (BM) and in peripheral blood (PB), and it is used as a powerful and independent marker of minimal residual disease (MRD); we have determined the expression levels of the WT1 by real-time quantitative polymerase chain reaction (RQ-PCR) in PB and BM in 126 newly diagnosed AML patients. Materials and Methods: This study was done in molecular pathology and cancer research center from April 2014 to June 2015, RQ-PCR method was used to determine the WT1 gene expression in BM and/or PB samples from 126 patients of AML, we cloned both WT1 and ABL genes for creating a standard curve, and we calculate copy number of WT1 genes in patients. Results: A total of 126 AML patients consist of 70 males (55.6%) and 56 females (44.4%), with a median age of 26 years; 104 (81%) patients out of 126 show overexpression of WT1 gene. We also concomitant monitoring of fusion transcripts (PML RARa, AML1-ETO, MLL-MLL, CBFb-MYH11, or DEK-CAN) in our patients, the AML1-ETO group showing remarkably low levels of WT1 compared with other fusion transcript and the CBFB-MYH11 showing high levels of WT1. Conclusion: We conclude that WT1 expression by RQ-PCR in AML patients may be employed as an independent tool to detect MRD in the majority of normal karyotype AML patients. [ABSTRACT FROM AUTHOR]

Background: The Wilms tumor 1 (WT1) gene is originally defined as a tumor suppressor gene and a transcription factor that overexpressed in leukemic cells. It is highly expressed in more than 80% of acute myeloid leukemia (AML) patients, both in bone marrow (BM) and in peripheral blood (PB), and it is used as a powerful and independent marker of minimal residual disease (MRD); we have determined the expression levels of the WT1 by real-time quantitative polymerase chain reaction (RQ-PCR) in PB and BM in 126 newly diagnosed AML patients. Materials and Methods: This study was done in molecular pathology and cancer research center from April 2014 to June 2015, RQ-PCR method was used to determine the WT1 gene expression in BM and/or PB samples from 126 patients of AML, we cloned both WT1 and ABL genes for creating a standard curve, and we calculate copy number of WT1 genes in patients. Results: A total of 126 AML patients consist of 70 males (55.6%) and 56 females (44.4%), with a median age of 26 years; 104 (81%) patients out of 126 show overexpression of WT1 gene. We also concomitant monitoring of fusion transcripts (PML RARa, AML1-ETO, MLL-MLL, CBFb-MYH11, or DEK-CAN) in our patients, the AML1-ETO group showing remarkably low levels of WT1 compared with other fusion transcript and the CBFB-MYH11 showing high levels of WT1. Conclusion: We conclude that WT1 expression by RQ-PCR in AML patients may be employed as an independent tool to detect MRD in the majority of normal karyotype AML patients.

Abstract: Objectives.: To determine the WT1 expression level in tumor tissues from 774 women with an epithelial ovarian tumor. Secondly, to evaluate whether WT1 tissue expression levels correlate with clinico-pathological parameters and finally to investigate the prognostic value of WT1 expression levels in ovarian cancer (OC) patients. Methods.: Using tissue array we analyzed the WT1 expression level in tissues from 186 women with Low Malignant Potential tumors (LMP) (160 stage I, 5 stage II and 21 stage III) and 560 OC patients (160 stage I, 60 stage II, 289 stage III and 51 stage IV). Results.: Using 10% as cut-off level for WT1 overexpression an overall of 19% LMPs and 17% carcinomas, respectively, were found positive. For both, a higher proportion of positive tumors was found in the serous subtype compared to other histological subtypes (p <0.0001). Kaplan–Meier survival analysis stratified by FIGO stage performed on cases using a 10% cut-off showed a shorter disease specific survival in patients with a positive WT1 expression in the tumor tissue. In a Cox survival analysis including 559 stage I to IV OC prognostic factors included FIGO stage (II vs. I: HR=2.74, 95% CI: 1.42–5.29; III vs. II: HR=2.23, 95% CI: 1.49–3.36; IV vs. III: HR=1.75, 95% CI: 1.25–2.44), residual tumor after primary surgery (HR=2.82, 95% CI: 1.87–4.26), age at diagnosis (HR=1.02, 95% CI: 1.01–1.03), histological grade 3 of tumor versus grade 1 (grade 2 vs. grade 1: HR=1.31, 95% CI: 0.95–1.81; grade 3 vs. grade 1: HR=1.51, 95% CI: 1.08–2.09) and other histological tumor types vs. serous (mucinous vs. serous: HR=0.91, 95% CI: 0.53–1.56; endometrioid vs. serous: HR=1.02, 95% CI: 0.69–1.50; other histological types vs. serous: HR=1.40, 95% CI: 1.01–1.95). WT1 expression (HR=1.22, 95% CI: 0.94–1.59) had statistically no significant independent impact on survival. Conclusion.: In conclusion, based on our analyses we found that WT1 expression in clinical settings may be of limited prognostic value in Danish OC patients. [Copyright &y& Elsevier]

An important measure to ensure successful follow-up in patients with allogeneic stem cell transplant is to evaluate for engraftment. Recent studies have shown that detecting minimal residual disease is important in order to predict early clinical relapse. We followed 88 leukemic patients with pre- and posttransplant Wilms tumor gene (WT1) levels to predict relapse and variable number of tandem repeats (VNTR) for engraftment. We have found that high pretransplant WT1 levels correlated significantly with relapse in all patient groups, but more significantly in the acute nonlymphoblastic leukemia (ANLL) patients. Posttransplant WT1 level correlated with VNTR status such that low WT1 is associated invariably with VNTR of 100% donor origin, while high WT1 is associated with VNTR of 20%. The association is significant in all patients, specifically in ANLL patients. In this preliminary study, we demonstrate that patients harboring detectable levels of WT1 prior to stem cell transplant have a higher chance of relapse, and posttransplant WT1 and VNTR status appeared to be dependant parameters predicting relapse when present in the posttransplant period. By combining 2 highly sensitive molecular techniques, we have found that this combined technique provided us with a promising alternative for overcoming the limitations imposed by each separate procedure. More studies are necessary beforewe can come to any significant conclusions. [ABSTRACT FROM AUTHOR]

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects.These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS. [ABSTRACT FROM AUTHOR]

Wilms tumor gene (WT1) expression occurs in various malignancies including adult leukemia. WT1 expression was studied in children with acute leukemia according to morphological types and immunophenotypes. RT-PCR was used to examine relative level of WT1 transcripts from the peripheral blood of 15 children diagnosed with acute leukemia: 12 acute lymphoblastic leukemias (ALLs) and 3 acute myelogenous leukemias (AMLs); 8 ALLs newly diagnosed, 2 ALLs in first marrow relapse, 2 ALLs in remission over 2 years, 2 AMLs newly diagnosed, and 1 AML in second marrow relapse. Six healthy adult volunteers were studied for controls. WT1 was detectable in 7 out of 10 ALLs and all 3 AMLs, but not in 2 ALLs in remission and the controls. The expression levels were higher for AMLs than for ALLs. According to the types of ALL, WT1 was detectable in 2 out of 2 non-T group II, 4 out of 6 non-T group III, but not in one CD20 + non-T group IV, while one T-ALL showed a relatively high level. WT1 expression was detectable more frequently in ALL-L than in ALL-L and with higher levels for ALL-L . WT1 expression was frequently noted in children with acute leukemia. The results suggest that WT1 transcripts may prove to be a significant tumor marker, possibly as an MRD monitor in evaluating remission status and early relapse, and may also prove to be useful in predicting outcomes in acute leukemia in children. 2 1 2. [ABSTRACT FROM AUTHOR]

We previously demonstrated maternal monoallelic expression of the Wilms tumor suppressor gene, WT1, in about half of pre-term placental villus and fetal brain tissues examined. There were two alternative explanations for this pattern of the WT1 expression, i.e., an imprinting polymorphism vs. a developmental stage-dependent switching from monoallelic to biallelic expression of the gene. To investigate these possibilities, we examined WT1 expression in a larger number of villus samples (46 samples) with gestational ages ranging from 4 to 21 weeks, using reverse transcriptase-based polymerase chain reaction (RT-PCR) to amplify the sequences for polymorphic sites in the 3′-untranslated region (UTR) of WT1. Maternal monoallelic expression was observed in 7 (39%) of 18 samples informative for the polymorphism, while the expression of the remaining 11 samples was biallelic. In addition, there was no correlation between expression patterns and gestational ages of the samples. The results indicate that the pattern of expression (monoallelic vs. biallelic) is polymorphic. The expression patterns were also studied in five different organs from a 21-week-old fetus, showing monoallelic expression only in the placenta and biallelic expression in other organs (heart, lung, liver and intestine). The finding supports the tissue specificity of the WT1 monoallelic expression. [ABSTRACT FROM AUTHOR]

Wilms tumor gene (WT1) is used as a marker for the diagnosis and prognosis of ovarian cancer. However, the molecular mechanisms involving WT1 in ovarian cancer require further study. Herein, we used bioinformatics and other methods to identify important pathways and hub genes in ovarian cancer affected by WT1. The results showed that WT1 is highly expressed in ovarian cancer and is closely related to the overall survival and progression-free survival (PFS) of ovarian cancer. In ovarian cancer cell line SKOV3, WT1 downregulation increased the mRNA expression of 638 genes and decreased the mRNA expression of 512 genes, which were enriched in the FoxO, AMPK, and the Hippo signaling pathways. The STRING online tool and Cytoscape software were used to construct a Protein-protein interaction (PPI) network and for Module analysis, and 18 differentially expressed genes (DEGs) were selected. Kaplan-Meier plotter analysis revealed that 16 of 18 genes were related to prognosis. Analysis of GEPIA datasets indicated that 7 of 16 genes were differentially expressed in ovarian cancer tissues and in normal tissues. The expression of IGFBP1 and FBN1 genes increased significantly after WT1 interference, while the expression of the SERPINA1 gene decreased significantly. The correlation between WT1 expression and that of these three genes was consistent with that of ovarian cancer tissues and normal tissues. According to the GeneMANIA online website analysis, there were complex interactions between WT1, IGFBP1, FBN1, SERPINA1, and 20 other genes. In conclusion, we have identified important signaling pathways involving WT1 that affect ovarian cancer, and distinguished three differentially expressed genes regulated by WT1 associated with the prognosis of ovarian cancer. Our findings provide evidence outlining mechanisms involving WT1 gene expression in ovarian cancer and provides a rational for novel treatment of ovarian cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meng, Cao, Dong, Zhang, Ji and Wang.)

Mestrallet G, Bertholet-Thomas A, Ranchin B, Bouvier R, Frappaz D, Cochat P. Recurrence of a dysgerminoma in Frasier syndrome. Pediatr Transplantation 2011: 15:e53-e55. © 2010 John Wiley & Sons A/S. FS is an inherited disease characterized by male pseudohermaphroditism and glomerular involvement leading to end-stage renal disease during adolescence or early adulthood (J Pediatr 1964:64:740). The FS phenotype in 46,XY patients consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma, and development of renal failure in the second decade of life. FS is caused by heterozygous mutation in intron 9 of the WT1 leading to a change in splicing that results in loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/−KTS isoforms that is critical for proper gonadal and renal development (Nat Genet 1997:17:467; Hum Mol Genet 1998:7:709). We report on a patient followed for FS revealed by acute peritoneal syndrome because of ovarian dysgerminoma. Therapeutic options had led to an unusual course with recurrent neoplastic disease after renal transplantation. [ABSTRACT FROM AUTHOR]

There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital development and mutations in this gene have been associated with DDS. DDS should be considered in the differential diagnosis of newborns with genital anomalies. In contrast to other conditions with 46,XY disorders of sex development, individuals with DDS often have duplicated genital organs (a double vagina, cervix or uterus). A double uterus has not yet been reported with 1390G>A (Arg464 Asn) mutation. However, duplicated genitals have been reported with other genetic mutations in patients with DDS. The duplicated genitals in DDS may be associated with low anti-Mullerian hormone (AMH) secretion. Measurement of the AMH levels may add to our understanding of variations in genital development and their abnormalities in disorders such as DDS. In conclusion, this is first case of low level of AMH and double uterus in 1390G>A (Arg464 Asn) mutations of DDS male.