Loss of heterozygosity for chromosomes 16q in Wilms tumors predicts outcomes:A meta-analysis

BACKGROUND The research findings suggest that the prognosis of children with Wilms tumor(WT)is affected by various factors.Some scholars have indicated that loss of heterozygosity(LOH)on chromosome 16q is associated with a poor prognosis in patients with WT.AIM To further elucidate this relationship,we conducted a meta-analysis.METHODS This meta-analysis was registered in INPLASY(INPLASY2023100060).We systematically searched databases including Embase,PubMed,Web of Science,Cochrane,and Google Scholar up to May 31,2020,for randomized trials reporting any intrapartum fetal surveillance approach.The meta-analysis was performed within a frequentist framework,and the quality and network inconsistency of trials were assessed.Odds ratios and 95%CIs were calculated to report the relationship between event-free survival and 16q LOH in patients with WT.RESULTS Eleven cohort studies were included in this meta-analysis to estimate the relationship between event-free survival and 16q LOH in patients with WT(I^(2)=25%,P<0.001).As expected,16q LOH can serve as an effective predictor of eventfree survival in patients with WT(risk ratio=1.95,95%CI:1.52–2.49,P<0.001).CONCLUSION In pediatric patients with WT,there exists a partial correlation between 16q LOH and an unfavorable treatment prognosis.Clinical detection of 16q chromosome LOH warrants increased attention to the patient’s prognosis.

Diagnosis and treatment of Wilms tumor

We collected a medical record of“Wilms’tumor”in the Department of Urology at the Third Affiliated Hospital of Inner Mongolia Medical University,and discussed the diagnosis,auxiliary examination and treatment of the disease.We hope to expand clinical thinking,improve our diagnosis and treatment of the disease through data analysis.

Wilm′s tumor gene1肽疫苗Galinpepimut-S在肿瘤免疫治疗中的应用

目的为Wilm′s tumor gene1(WT1)肽疫苗Galinpepimut-S(GPS)用于肿瘤免疫治疗的后续研究提供参考。方法采用计算机检索中国知网、PubMed等数据库自建库起至2022年12月的肿瘤免疫治疗相关文献,总结GPS在肿瘤免疫治疗中的应用现状。结果GPS能激发自身免疫系统,对WT1抗原产生强烈免疫反应而发挥抗肿瘤作用,在卵巢癌、恶性胸膜间皮瘤、急性髓系白血病、多发性骨髓瘤的治疗中均显示出较好的疗效。结论以GPS为代表的肿瘤疫苗是未来肿瘤治疗的重要方向,需进一步进行临床研究,以获取更多数据。

Expression of vascular endothelial growth factor （VEGF） and VEGF-C in serum and tissue of Wilms tumor

Background Angiogenesis and lymphogenesis which were promoted by vascular endothelial growth factor （VEGF） and VEGF-C are important in the growth and metastasis of solid tumors. The high level of VEGF and VEGF-C were distributed in numerous types of cancers, but their distribution and expression in Wilms tumor, the most common pediatric tumor of the kidney, was unclear. Methods To learn about the distribution, mass spectroscopy and immunohistochemistry were used to measure the level of VEGF and VEGF-C in serum and tissue of Wilms tumor. Results The expression level of VEGF in serum of Wilms tumor was the same as in pre-surgery and control, so it was the same case of VEGF-C. Both of these factors were chiefly located in Wilms tumor tissue, but not in borderline and normal. In addition, the higher clinical staging and histopathologic grading were important elements in high expression of VEGF and VEGF-C. Gender, age and the size of tumor have not certainly been implicated in expression level of VEGF and VEGF-C. Conclusions The lymph node metastasis and growth of tumors resulted from angiogenesis and lymphogenesis which were promoted by VEGF and VEGF-C in Wilms tumor. The autocrine and paracrine process of VEGF and VEGF-C were the principal contributor to specific tissues of Wilms tumor but not to the entire body.

Association between Long Interspersed Nuclear Element-1 Methylation and Relative Telomere Length in Wilms Tumor

Background： DNA hypomethylation of long interspersed nuclear elements- 1 （LINEs- 1 ） occurs during carcinogenesis, whereas intbmaation addressing LINE-1 methylation in Wilms tumor （WT） is limited. The main purpose of our study was to quantity, LINE-1 methylation levels and evaluate their relationship with relative telomere length （TL） in WT. Methods： We investigated LINE-1 methylation and relative TL using bisulfite-polymerase chain reaction （PCR） pyrosequencing and quantitative PCR, respectively, in 20 WT tissues, 10 normal kidney tissues and a WT cell line. Significant changes were analyzed by t-tests. Results： LINE-1 methylation levels were significantly lower （P 〈 0.05） and relative TLs were sigmificantly shorter （P 〈 0.05） in WT compared with normal kidney. There was a significant positive relationship between LINE- 1 methylation and relative TL in WT （r = 0.671, P = 0.001 ）. LINE- 1 Methylation levels were significantly associated with global DNA methylation （r = 0.332, P 〈 0.01 ）. In addition, relative TL was shortened and LINE- 1 methylation was decreased in a WT cell line treated with the hypomethylating agent 5-aza-2＇-deoxycytidine compared with untreated WT cell line. Conclusion： These results suggest that LINE-1 hypomethylation is common and may be linked to telomere shortening in WT.

Management of Wilms tumor with intravenous thrombus in children:a single center experience

Background Wilms tumor tends to grow into vena cava,even invade atrium,which increased operating difficulty and frequency of surgical complications.Methods Forty-two patients of Wilms tumor with intravenous thrombus were retrospective studied.The diagnosis and therapy were discussed according to the medical records and interrelated literatures.Results Forty-two children with thrombus were diagnosed by computed tomography and 41 cases by ultrasound simultaneously.36 children had received preoperative chemotherapy.Surgical resection was performed in all patients.Cardiopulmonary bypass was used for the removal of the intra-atrial thrombus in 5 patients.There were no surgical complications occurred.The patients received chemotherapy and radiotherapy according to clinical staging by National Wilms'Tumor Study(NWTS)-4 or NWTS-5.34 patients were successfully followed up,32 patients survive at present,including one who has been followed up more than 20 years since operation.Conclusion Standardized sequential treatment,including preoperative chemotherapy and radiotherapy,nephrectomy combining resection of thrombus,postoperative adjuvant therapy,is the mainstay of treatment of Wilms tumor with intravenous thrombus.

Expression and significance of p53,nm23 and p16 in Wilms' tumor of children

We studied 22 Wilms’tumors of children immunohistochemically.We’ve found that the positive rate of p53 in slices was 31.8％ (7),of nm23 was 50％ (11),and of p16 was 86.4％ (19).It suggested that mutation rate of p53 was high in tumors,expression of nm23 in favorite histology(FH)was higher than that in unfavorite histology(UFH) group,and p16 showed very high positive rate in tumors.All of the three showed no relation with sex,age,or pathological type.So each one may be useful in clinic to evaluate pathogenesis and prognosis.

Spontaneous xenogeneic GvHD in Wilms'tumor Patient-Derived xenograft models and potential solutions

Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(TILs)can induce xenogeneic graft-versus-host disease(xGvHD)following engraftment and expansion of the TILs inside the animal body.Wilms’tumor(WT)has not been recognized as a lymphocyte-predominant tumor.However,3 consecutive generations of NOG mice bearing WT patient-derived xenografts(PDX)xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention.In the initial generation,dermatitis,auto-amputation of digits,weight loss,lymphadenopathy,hepatitis,and interstitial pneumonitis were observed.Despite antibiotic treatment,no response was noticed,and thus the animals were prematurely euthanized(day 47 posttransplantation).Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor,whereas no microbial infection or lymphoproliferative disorder was found.Mice of the next generation that lived longer(91 days)developed sclerotic skin changes and more severe pneumonitis.Cutaneous symptoms were milder in the last generation.The xenografts of the last 2 generations also contained TILs,and lacked lymphoproliferative transformation.The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD.While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts,this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication.

Osteopathia striata with cranial sclerosis, Wilms' tumor and the WTX gene

Osteopathia striata with cranial sclerosis(OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline mutations in the FAM123 B /WTX /AMER1 gene, mapped to chromosome Xq11.2, cause both the familial and sporadic forms of OSCS. Intriguingly, the WTX gene was already known as a putative tumor suppressor gene, since in 2007 Rivera et al had reported inactivating WTX mutations in Wilms' tumor(WT), the most frequent renal tumor of childhood. Here we review the heterogeneous clinical presentation of OSCS patients and the involvement of WTX anomalies in OSCS and in WT.

Unilateral Ptosis in a Child with Wilm’s Tumor Induced by Vincristine

Vincristine is a chemotherapy drug belonging to the group of Vinca alkaloids which also includes vinblastine and vindesine. It is used in hematological malignancies and solid tumors. The Vinca alkaloids are neurotoxic, usually causing peripheral neuropathy, and rarely cranial neuropathies. We report a case of a 33-month-old male child diagnosed with Wilms’ tumor, who had an isolated unilateral right ptosis following vincristine, with a good improvement after stopping it.

Prognostic Factors of Wilms＇ Tumor Complicated with Nephroblastomatosis

Nephrogenic rests （NRs） are abnormally persistent clusters of embryonal cells, representing microscopic dysplasias of the developing kidney. NRs are found in approximately 1% of infant kidneys at autopsy. Nephroblastomatosis signifies the presence of multiple or diffuse NRs. Both NRs and nephroblastomatosis were known as precursor lesions of Wilms tumor,Nephroblastomatosis can be classified into four categories： Perilobar （PEN R only）; i ntralobar （I LNR only）; combined （PLNR and ILNR）; and universal. The diagnosis and treatment of Wilms＂ tumor have been improved constantly and achieved common sense. However, little information is available regarding Wilms＂ tumor associated with nephroblastomatosis for lower prevalence. This study aimed to investigate the prognostic factors of Wilms＇ tumor associated with nephroblastomatosis.

Discovery and identification of serum biomarkers of Wilms＇ tumor in mice using proteomics technology

Background Wilms＇ tumor （nephroblastoma） is a cancer of the kidneys that occurs typically in children and rarely in adults. Early diagnosis is very important for the treatment and prognosis of the disease. The aim of our study was to discover and identify potential non-invasive and convenient biomarkers for the diagnosis of Wilms＇ tumor. Methods Nude mice were used to construct a Wilms＇ tumor model by injecting nephroblastoma cells into their bilateral abdomen. We collected 94 serum samples from mice consisting of 45 samples with Wilms＇ tumor and 49 controls. The serum proteomic profiles of the samples were analyzed via surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. The candidate biomarkers were purified by high-performance liquid chromatography, identified by liquid chromatography-mass spectrometry, and validated using ProteinChip immunoassays. Results We finally retrieved two differential proteins （mlz 4509.2; 6207.9）, which were identified as apolipoprotein A-II and polyubiquitin, respectively. The expression of apolipoprotein A-II was higher in the Wilms＇ tumor group than in the control group （P 〈0.01）. By contrast, the expression of polyubiquitin was lower in the Wilms＇ tumor group than in the control group. Conclusion Apolipoprotein A-II and polyubiquitin may be used as potential biomarkers for nephroblastoma in children, and the analysis of apolipoprotein A-II may help diagnose and treat Wilms＇ tumor.

Nephroblastoma: Radiological and Pathological Diagnosis of a Case with Liver Metastases

Nephroblastoma is one of the most common causes of abdominal-pelvic mass in children. It still raises a diagnostic problem because of the wide variety of causes of abdominal-pelvic mass but also because of the delays in consultation in sub-Saharan black Africa and consequently the discovery of the mass at a very late and sometimes metastatic stage. Yet nephroblastoma is a very chemo-sensitive malignancy requiring diagnosis at an early stage;a procedure in which medical imaging is essential. We report the case of a large abdominal-pelvic mass in a three-year-old girl in whom the abdominal-pelvic CT allowed to diagnose nephroblastoma with liver metastases. Our objective is to demonstrate the contribution of computed tomography in the diagnosis of large abdominal-pelvic mass of the child and discuss other causes of abdominal-pelvic mass of the child.

Identification and analysis of mutations in WTX and WT1 genes in peripheral blood and tumor tissue of children with Wilms＇ tumor

Background Wilms＇ tumor （nephroblastoma） is the most common pediatric kidney cancer. Only one Wilms＇ tumor gene is known, WT1 at 11p13, which is mutated in 5%-10% of Wilms＇ tumors. Recently, mutations were reported in WTX at Xq11.1 in Wilms＇ tumors. This study investigated the mutation proportion, type, and distribution in WTX and WT1 in children with Wilms＇ tumor. The role of WTX/WT1 in the development of Wilms＇ tumor, and the relationship between clinical phenotype and genotype, were also studied. Methods Wilms＇ tumor specimens （blood samples from 70 patients and tumor tissue samples from 52 patients） were used. A long fragment of WTXand 10 exons and intron sequences of WT1 were amplified by polymerase chain reaction （PCR） from extracted genomic DNA and sequenced. A chi-square test compared the difference between the W-/-X mutation group and the no mutation group. The relationship between the mutations and clinical phenotype was analyzed. Results W7X mutations were found in 5/52 tumor tissues and in 2/70 peripheral blood samples （five cases in total, all point mutations）. Two patients had a WTX mutation in both samples. WT1 mutations were found in 2/52 tumor tissues and in 4/70 peripheral blood samples （five cases in total, all point mutations）. One patient had a WT1 mutation in both samples. Ten cases had WTX or WT1 mutation （19.2% of Wilms＇ tumors）. No overlapping WTX and WTI mutations were found. No significant differences in clinical parameters were found between patients with and without a W7X mutation. Conclusions WTX mutations occur early in Wilms＇ tumor development, but at a low proportion. There was no evidence that WTX is the main cause of Wilms＇ tumor. Clinical parameters of patients with WTX mutations are not related to the mutation, indicating a limited impact of WTX on tumor progression. WTX and WT1 mutations occur independently, suggesting a relationship between their gene products.

Detection of biomarkers in children with Wilms＇ tumor using proteinchip technology

Wilms＇ tumor is the most common pediatric tumor of the kidney. The most important factor affecting long term survival of this malignancy is recurrence after surgery. Early diagnosis, treatment and regular follow-up are critical to prevent recurrence and improve long-term survival rate. Currently,

Graft-versus-leukemia effects of Wilms＇ tumor 1 protein-specific cytotoxic T lymphocytes in patients with chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Background The role of Wilms＇ tumor 1 protein （WT1）-specific cytotoxic T cells （CTL） in eradicating chronic myeloid leukemia （CML） cells is to be established. The aim of this study was to determine whether WT1 contributed to the graft-versus-leukemia effects （GVLE） for CML following allogeneic hematopoietic stem cell transplantation （HSCT）. Methods High-resolution human leukocyte antigen （HLA） class I genotyping was performed by sequence-specific polymerase chain reaction （PCR）. Fifteen HLA-A~＊2402 patients with CML who underwent allogeneic HSCT were enrolled in this study. We monitored the frequency of WT1-specific CTL by pentamer assay and the molecular minimal residual disease by real-time quantitative PCR.Results A CD8＋ T-cell response to WT1 was observed in 14 of 15 patients after HSCT. The median frequencies of WT1-CTL were 0.54%, 0.62%, 0.81% and 1.28% （%CD8） on days 30, 60, 90 and 180, respectively. The median frequency of WT1-CTL （1.38%） in patients with molecular remission （MoR） was significantly higher than that in those without MoR （0.38%） on day 30, while no significant differences between them were detected on days 60, 90 and 180. The increase of WT1-CTL was associated with a decrease in bcr-abl expression and MoR; and the decrease of WT1-CTL was associated with an increase in bcr-abl expression, suggesting a WT1 -driven GVL effect. WT1-CTL had a predominant effector-memory phenotype （CD45RO＋CD27-CD57＋）.Conclusions The emergence of WT1-CTL with an effector-memory phenotype is associated with GVLE in CML patients after HSCT. This will pave the way for the WT1 vaccines to enhance GVLE after HSCT in CML.

Interaction of Human Genes WT1 and CML28 in Leukemic Cells

The molecular pathogenesis of leukemia is poorly understood. Earlier studies have shown both Wilms＇ tumor 1 suppressor gene （WT1） and CML28 abnormally expressed in malignant diseases of the hematopoietic system and WT1 played an important role in leukemogenesis. However, the rela- tionship between molecular CML28 and WT1 has not been reported. Here we described the use of small interfering RNA （siRNA） against WT1 and CML28 in leukemic cell line K562 to examine the interac- tion between CML28 and WT1. WT1 and CML28 gene expression in transfected K562 cells was de- tected by using RQ-PCR and Western blotting. K562 cells transfected with WTI-siRNA could greatly decrease both mRNA and protein expression levels of WT1 and CML28. In contrast, CML28-siRNA did not exert effect on WT1. Further, subcellular co-localization assay showed that the two proteins could co-localize in the cytoplasm of K562 cells, but WT1/CML28 complexes were not detected by us- ing immunoprecipitation. It was suggested that there exists the relationship between CML28 and WT1. CML28 may be a downstream target molecule of WT1 and regulated by WT1, which will provide im- portant clues for further study on the role of CML28 and WT1 in leukemic cells.

Wilms’tumor gene(WT1)is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Aim:The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia(ALL).Methods:We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells vs.primary leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL cases.We also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159,GSE13351,and GSE13159.Results:Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements(MLL-R)express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ALL.Notably,MLL-R^(+)patients exhibited>6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined(P<0.0001).Our findings in 97 MLL-R^(+)infant B-lineage ALL cases uniquely demonstrated that WT1 is expressed at 1.5-4.2-fold higher levels in MLL-R^(+)infant leukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow cells.Furthermore,our study demonstrates for the first time that the WT1-regulated EWSR1,TP53,U2AF2,and WTAP genes(i.e.,WT1 interactome)were differentially upregulated in MLL-R^(+)leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R^(+)pediatric B-lineage ALL.These novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R^(+)pediatric B-lineage ALL,including MLL-R^(+)infant ALL.Furthermore,our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had significantly higher WT1 expression when compared to normal hematopoietic cells.Finally,our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primary leukemia cells from newly diagnosed B-lineage ALL patients(P=0.001).Conclusion:Our findings indicate that the WT1 gene product may serve as a target for immunotherapy in high risk/poor prognosis subsets of newly diagnosed as well as relapsed pediatric B-lineage ALL.Our findings also significantly expand the current knowledge of WT1 expression in T-lineage ALL and provide new evidence that WT1 gene and its interactome are expressed in T-lineage ALL cells at significantly higher levels than in normal hematopoietic cells.This previously unknown differential expression profile uniquely indicates that the protein product of WT1 would be an attractive molecular target for treatment of T-lineage ALL as well.

Expression and clinicopathologic significance of RASSF1A and WT1 in recurrent epithelial ovarian cancer

Objective To explore the expression and clinicopathological significance of RASSF1A and WT1 in recurrent epithelial ovarian cancer.Methods Sixty-three cases of patients with pathologically confirmed epithelial ovarian cancer were collected in the department of Gynaecology and Obsterics of the North China University of Technology from January 2013 to December 2018.The expression of RASSF1A and WT1 were measured by IHC staining.The relation of these proteins with ovarian cancer was also analyzed.Results Compared with non-recurrent group(46.4%),the positive expression rate of RASSF1A was 17.1%in recurrent group.The positive expression rate of WT1 was 74.3%and higher than the rate of 42.8%in non-recurrent group.The reducing expression of RASSF1A was related to clinical stage,differentiation,and with ascites(P<0.05).The increasing expression of WT1 was related to pathological type,clinical stage,histological differentiation,with ascites,and lymph node metastasis(P<0.05).Conclusion Low expression of RASSF1A and high expression of WT1 may be related to recurrent epithelial ovarian cancer.

Effects of Bufalin on Up-regulating Methylation of Wilm's Tumor 1 Gene in Human Erythroid Leukemic Cells

Objective To explore the effects of bufalin on inhibiting proliferation, up-regulating methylation of Wilm’ tumor 1 gene (WT1) as well as its possible mechanisms in human erythroid leukemic (HEL) cells. Methods The HEL cells were treated with bufalin at various concentrations to observe cellular morphology, proliferation assay and cell cycle. The mRNA and protein expression levels of WT1 were detected by reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunocytochemistry, DNA methylation of WT1 and protein expression levels of DNA methyltransferase 3a (DNMT3a) and DNMT3b were analyzed by methylation-specific PCR, and Western blot respectively. Results The bufalin was effective to inhibit proliferation of HEL cells in a dose-dependent manner, their suppression rates were from 23.4%±2.1% to 87.2%±5.4% with an half maximal inhibit concentration (IC50) of 0.046 μmol/L. Typical apoptosis morphology was observed in bufalin-treated HEL cells. The proliferation index of cell cycle decreased from 76.4%±1.9% to 49.7%±1.3%. The expression levels of WT1 mRNA and its protein reduced gradually with increasing doses of bufalin, meanwhile, the methylation status of WT1 gene changed from unmethylated into partially or totally methylated. While, the expression levels of DNMT3a and DNMT3b protein gradually increased by bufalin treatment in a dose-dependent manner. Conclusions Bufalin can not only significantly inhibit the proliferation of HEL cells and arrest cell cycle at G0/G1 phase, but also induce cellular apoptosis and down-regulate the expression level of WT1. Our results provide the evidence of bufalin for anti-leukemia, its mechanism may involve in increasing WT1 methylation status which is related to the up-regulation of DNMT3a and DNMT3b proteins in erythroid leukemic HEL cells.