Identification and Validation of Lipid Metabolism Gene FASN-Associated miRNA in Wilms Tumor.

miRNA has been a research hotspot in recent years and its scope of action is very wide, involving the regulation of cell proliferation, differentiation, apoptosis, and other biological behaviors. This study intends to explore the role of miRNA in the lipid metabolism and development of Wilms tumor (WT) by detecting and analyzing the differences in the expression profiles of miRNAs between the tumor and adjacent normal tissue. Gene detection was performed in tumor tissues and adjacent normal tissues of three cases of WT to screen differentially expressed miRNAs (DEMs). According to our previous research, FASN, which participates in the lipid metabolism pathway, may be a target of WT. The starBase database was used to predict FASN-targeted miRNAs. The above two groups of miRNAs were intersected to obtain FASN-targeted DEMs and then GO Ontology (GO) functional enrichment analysis of FASN-targeted DEMs was performed. Finally, the FASN-targeted DEMs were compared and further verified by qRT‒PCR. Through gene sequencing and differential analysis, 287 DEMs were obtained, including 132 upregulated and 155 downregulated miRNAs. The top ten DEMs were all downregulated. Fourteen miRNAs targeted by the lipid metabolism-related gene FASN were predicted by starBase. After intersection with the DEMs, three miRNAs were finally obtained, namely, miR-107, miR-27a-3p, and miR-335-5p. GO enrichment analysis was mainly concentrated in the Parkin-FBXW7-Cul1 ubiquitin ligase complex and response to prostaglandin E. Further experimental verification showed that miR-27a-3p was significantly correlated with WT (P = 0.0018). Imbalanced expression of miRNAs may be involved in the occurrence and development of WT through lipid metabolism. The expression of miR-27a-3p is related to the malignant degree of WT, and it may become the target of diagnosis, prognosis, and treatment of WT in the later stage.

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children's Oncology Group.

BACKGROUND: A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event-free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. METHODS: The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia. RESULTS: In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49-8.78 years). The median follow-up was 4.49 years (range, 1.67-8.01 years). The underlying diagnosis included Beckwith-Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys-Drash syndrome in 1 patient, and Simpson-Golabi-Behmel syndrome in 1 patient. The 4-year EFS and OS rates were 94% (95% CI, 85.2%-100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low-risk in 13 patients (including the 2 complete responders), intermediate-risk in 15 patients, and high-risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%). CONCLUSIONS: A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.

Wilms tumor in horseshoe kidney with extensive vascular thrombosis: A case report.

INTRODUCTION AND IMPORTANCE: Wilms tumor (WT), a prevalent pediatric renal malignancy (7 %), frequently intertwines with genitourinary anomalies. This unique report presents a case of WT combined with horseshoe Kidney and an extending atrial thrombus, emphasizing critical management considerations. CASE PRESENTATION: A 3-year-old boy, experiencing flank pain and weight loss, manifested a WT linked to horseshoe Kidney, accompanied by an atrial thrombus. Neoadjuvant chemotherapy downsized the tumor and thrombus, enabling successful surgical intervention. Post-surgery, 27 weeks of adjuvant chemotherapy were administered. Over three years, follow-up exhibited renal recovery, no recurrence, and clear CT scans. DISCUSSION: Prompt identification, precise imaging (via CT angiography), and multidisciplinary care are pivotal for managing WT in horseshoe Kidney cases. Preoperative chemotherapy notably reduced tumor and thrombus sizes, enhancing surgical feasibility. Long-term vigilance is essential for recurrence and treatment-related complications. CONCLUSION: Effectively managing WT in horseshoe Kidneys demands timely recognition, meticulous imaging, and collaborative management. Successful outcomes highlight preoperative chemotherapy's benefits and underscore extended monitoring's significance in confirming sustained recovery.

Molecular mechanism of Wilms' tumor (Wt1) (+/-KTS) variants promoting proliferation and migration of ovarian epithelial cells by bioinformatics analysis.

Epithelial ovarian cancer (EOC) is a gynecological disease with the highest mortality. With the lack of understanding of its pathogenesis, no accurate early diagnosis and screening method has been established for EOC. Studies revealed the multi-faceted function of Wilms' tumor (Wt1) genes in cancer, which may be related to the existence of multiple alternative splices. Our results show that Wt1 (+KTS) or Wt1 (-KTS) overexpression can significantly promote the proliferation and migration of human ovarian epithelial cells HOSEpiC, and Wt1 (+KTS) effects were more evident. To explore the Wt1 (+/-KTS) variant mechanism in HOSEpiC proliferation and migration and ovarian cancer (OC) occurrence and development, this study explored the differential regulation of Wt1 (+/-KTS) in HOSEpiC proliferation and migration by transcriptome sequencing. OC-related hub genes were screened by bioinformatics analysis to further explore the differential molecular mechanism of Wt1 (+/-KTS) in the occurrence of OC. Finally, we found that the regulation of Wt1 (+/-KTS) variants on the proliferation and migration of HOSEpiC may act through different genes and signaling pathways and screened out key genes and differentially regulated genes that regulate the malignant transformation of ovarian epithelial cells. The implementation of this study will provide new clues for the early diagnosis and precise treatment of OC.

A Metabonomic View on Wilms Tumor by High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy.

Pediatric cancer NMR-metabonomics might be a powerful tool to discover modified biochemical pathways in tumor development, improve cancer diagnosis, and, consequently, treatment. Wilms tumor (WT) is the most common kidney tumor in young children whose genetic and epigenetic abnormalities lead to cell metabolism alterations, but, so far, investigation of metabolic pathways in WT is scarce. We aimed to explore the high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) metabonomics of WT and normal kidney (NK) samples. For this study, 14 WT and 7 NK tissue samples were obtained from the same patients and analyzed. One-dimensional and two-dimensional HR-MAS NMR spectra were processed, and the one-dimensional NMR data were analyzed using chemometrics. Chemometrics enabled us to elucidate the most significant differences between the tumor and normal tissues and to discover intrinsic metabolite alterations in WT. The metabolic differences in WT tissues were revealed by a validated PLS-DA applied on HR-MAS T2-edited 1H-NMR and were assigned to 16 metabolites, such as lipids, glucose, and branched-chain amino acids (BCAAs), among others. The WT compared to NK samples showed 13 metabolites with increased concentrations and 3 metabolites with decreased concentrations. The relative BCAA concentrations were decreased in the WT while lipids, lactate, and glutamine/glutamate showed increased levels. Sixteen tissue metabolites distinguish the analyzed WT samples and point to altered glycolysis, glutaminolysis, TCA cycle, and lipid and BCAA metabolism in WT. Significant variation in the concentrations of metabolites, such as glutamine/glutamate, lipids, lactate, and BCAAs, was observed in WT and opened up a perspective for their further study and clinical validation.

Surgical removal of bilateral lung metastases from Wilms tumor via subxiphoid approach video-assisted thoracic surgery: a case report.

Background: Lung is the most common site of metastasis in pediatric patients with Wilms tumor (WT). For such patients, neoadjuvant chemotherapy before nephrectomy is recommended now. A considerable proportion of metastases will shrink in size after the chemotherapy. However, there are still some of them that are not sensitive to chemotherapy and require subsequent surgical resection. For pediatric patients with bilateral lung metastases from WT which are not sensitive to chemotherapy, the simultaneous surgical removal of bilateral lung tumors via one-stage surgery is problematic. These children typically require 2 separate surgeries to remove the bilateral lung metastases and improve their 5-year event-free survival (EFS) rate. There is no precedent in pediatric thoracic surgery for one-stage, bilateral, lung wedge resection via subxiphoid approach video-assisted thoracic surgery (SA-VATS). Case Description: In this article, we report on a successful SA-VATS performed on an 8-year-old boy whereby all of the bilateral lung metastases were completely resected. The operation was performed through 3 incisions under the xiphoid process and costal arch. No complications occurred after surgery. The patient's intraoperative blood loss was approximately 20 mL. Drainage tubes were indwelled in both pleural cavities which were removed on post-operative day (POD) 5 and POD 6. There was no recurrence at follow-up of about 4 months. Conclusions: This case presents a new option for thoracoscopic surgery which is safe and less invasive for patients with bilateral lung metastases from WT. Similar patients may benefit from the shorter time frame between the operation and other postoperative treatment.

Identification of key genes associated with cancer stem cell characteristics in Wilms' tumor based on bioinformatics analysis.

Background: Nephroblastoma, also known as Wilms' tumor (WT), remains one of the major causes of tumor-related deaths worldwide in children. Cancer stem cells (CSCs) are considered to be the main culprits in cancer resistance and disease recurrence, which are reported in multiple types of tumors. However, the research on CSCs in WT is limited. Therefore, our study aimed to identify the key genes related to CSCs in WT to provide new ideas for treating WT. Methods: The RNA-seq and clinical data of WT samples were obtained from the University of California Santa Cruz (UCSC) Xena database, which included 120 WT and six para-cancerous tissues. The mRNA stemness index (mRNAsi) based on mRNA expression was calculated to evaluate tumor stem cell characteristics in WT patients. A Kaplan-Meier (KM) analysis was performed to explore the clinical characteristics of the mRNAsi in WT. A weighted gene co-expression network analysis (WGCNA) was used to identify the key modules and genes related to the mRNAsi. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed to explore the signaling pathways based on the key genes. The expression levels of the key genes were validated by the Gene Expression Omnibus (GEO) database. Further, the important upstream genes were identified by DisNor and gene co-expression analyses. Results: The mRNAsi was significantly upregulated in WT (P=7.2e-05) and showed an upward trend in line with the pathological stage. Patients with lower mRNAsi scores had better overall survival (OS) than those with higher mRNAsi scores (P=0.0087). Eleven genes were defined as the key genes associated with the mRNAsi based on our WGCNA analysis [cor.MM (correlation. Module membership) >0.8 and cor.GS (correlation. Gene significance) >0.45] and were closely related to cell proliferation-related signaling pathways (P<0.05). Moreover, using protein interaction analysis, we identified ATM and CDKN1A as the key upstream regulatory genes of the 11 key genes. Conclusions: Our study showed that the mRNAsi score was a potential prognostic factors in WT and identified the upstream genes ATM and CDKN1A and 11 genes closely related to the mRNAsi, which may provide new insights for CSC-targeted therapy in WT and improve clinical outcomes for WT patients.

The Role of Ultrasonography forDiagnosing Wilms Tumor in Developing Country.

Background: Overall five-year survival rate of Wilm's Tumor (WT) in developing countries is still poor. Delayed diagnosis is one of the contributing factors, whereas early diagnosis is an important thing for the outcome. It is caused by the WT burden in developing countries that was not comparable with the number of facilities for diagnosis and treatment. Ultrasonography (USG) is the mandatory first-line imaging modality in children with a suspected abdominal mass and an overall sensitivity of 76%. Additionally, it can be found in many health facilities at a lower cost, quick, non-invasive, and carries no risk of radiation. Therefore, the relationship between USG and histopathology should be measured. Materials and Methods: A cross-sectional study with an analytical approach was performed in pediatric (0 untill 18 year of age) renal malignancy and neuroblastoma that admitted to Dr. Hasan Sadikin Hospital, Bandung between 2015-2018. Data were collected from medical records. Statistical analyses using Fisher exact test were done to determine the significance of the relationship between USG and histopathology. Results: Forty-three samples were obtained based on inclusion criteria, such as WT (n=33), neuroblastoma (n=6), renal clear cell carcinoma (n=2) and no specific type of renal malignancy (n=2). Fisher exact test revealed no-significant relationship between USG and histopathology with p-value > 0.05 Conclusion: There is no significant relationship between USG and histopathology. Therefore, centralized unity for USG interpretation is recommended.

Identification of a ferroptosis-related lncRNA signature with prognosis for Wilms tumor.

BACKGROUND: Wilms tumor (WT) is a widespread urologic tumor in children. Ferroptosis, on the other hand, is a novel form of cell death associated with tumor development. In this study, we aim to explore the predictability of ferroptosis-related biomarkers in estimating prognosis in WT patients. METHODS: To determine a link between ferroptosis-related gene expression and WT prognosis, we first collected RNA sequencing data and clinical information, involving 124 WT and 6 healthy tissue samples, from the TARGET database. Next, we screened the collected information for ferroptosis-related long non-coding RNA using Cox regression analysis, and constructed a signature model, as well as a nomogram, related to prognosis. Finally, we explored a potential link between ferroptosis-related lncRNA and tumor immunity and screened for possible immune checkpoints. RESULTS: We constructed a WT prognosis prediction signature containing 12 ferroptosis-related lncRNAs. The area under the curves values, from the ROC curves, predicting overall survival rates at the 1, 3-, and 5-year timepoints were 0.775, 0.867, and 0.891 respectively. Moreover, we generated a nomogram, using clinical features and risk scores, carrying a C-index value of 0.836, which suggested a high predictive value. We also demonstrated significant differences in tumor immunity between low- and high-risk WT patients, particularly in the presence of B cells, NK cells, Th1 cells, Treg cells, inflammation promoting, and type I and II IFN responses. In addition, we showed that immune checkpoints like SIRPA, ICOSLG, LAG3, PVRIG, NECTIN1, and SIRPB2 can serve as potential therapeutic targets for WT. CONCLUSIONS: Based on our analyses, we generated a ferroptosis-related lncRNA signature that can both estimate prognosis of WT patients and may provide basis for future WT therapy.

A long non-coding RNAs expression signature to improve prognostic prediction of Wilms tumor in children.

BACKGROUND: Wilms tumor (WT) is the most frequent malignancy of the kidney in children, and a subset of patients remains with a poor prognosis. This study aimed to identify key long non-coding RNAs (lncRNAs) related to prognosis and establish a genomic-clinicopathologic nomogram to predict survival in children with WT. METHODS: Clinical data of 124 WT patients and the relevant RNA sequencing data including lncRNAs expression signature of primary WT samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) Data Matrix. Then, lncRNAs associated with overall survival (OS) were identified through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. The risk scores of 124 participants were calculated, and survival analyses were performed between low- and high-risk groups. A genomic-clinicopathologic nomogram was then developed and evaluated by time-dependent receiver operating characteristic (ROC) curves, including the area under the curve (AUC), calibration curve, and decision curve analysis. Subsequently, bioinformatics analyses were performed to explore the potential molecular mechanisms that affect the prognosis of WT. The package "DESeq2" was used to identify differentially expressed protein-coding genes (DEPCGs) between groups. Gene Set Enrichment Analysis (GSEA) was applied to explore the differences in pathways enrichment. The analytical tools CIBERSORTx and ESTIMATE were used to investigate the discrepancies of the immune microenvironment. RESULTS: A total of 10 lncRNAs were selected as independent predictors associated with OS (P<0.05). Participants in the high-risk group had a significantly worse OS and event-free survival (EFS) than those in the low-risk group (P<2E-16 and P=2.03E-04, respectively). The risk score and 3 clinicopathological features (gender, cooperative group protocol, and stage) were identified to construct the nomogram (combined model) (P=5.11E-17). The combined model (1-year AUC: 0.9272, 3-year AUC: 0.9428, 5-year AUC: 0.9259) and risk score model (1-year AUC: 0.9285, 3-year AUC: 0.9399, 5-year AUC: 0.9266) displayed higher predictive accuracy than that of the other models. Subsequently, 105 DEPCGs were identified. The GSEA revealed 4 significant pathways. Analysis with CIBERSORTx demonstrated that monocytes, macrophages M1, activated dendritic cells, and resting mast cells had significant infiltration differences between groups. CONCLUSIONS: This study constructed a genomic-clinicopathologic nomogram, which might present a novel and efficient method for treating patients with WT.

Syndromic Wilms tumor: a review of predisposing conditions, surveillance and treatment.

Predisposing syndromes associated with an increased risk of Wilms tumor (WT) are responsible for 9-17% of all cases of the malignancy. Due to an earlier age at WT diagnosis and an increased incidence of bilateral and metachronous disease, management of syndromic WT warrants a distinct approach from that of non-syndromic WT. This review of English-language manuscripts about WT focuses on the most common syndromes, surveillance protocols and current treatment strategies. Highlighted syndromes include those associated with WT1, such as WAGR (Wilms-Aniridia-Genitourinary-mental Retardation), Denys-Drash syndrome (DDS), and Frasier syndrome, 11p15 defects, such as Beckwith-Wiedemann syndrome (BWS), among others. General surveillance guidelines include screening renal or abdominal ultrasound every 3-4 months until the age of 5 or 7, depending on the syndrome. Further, some of the predisposing conditions also increase the risk of other malignancies, such as gonadoblastoma and hepatoblastoma. With promising results for nephron-sparing surgery in bilateral non-syndromic WT, there are increasing reports and recommendations to pursue nephron-sparing for these patients who are at greater risk of bilateral, metachronous lesions. In addition to the loss of renal parenchyma from malignancy, many patients are at risk of developing renal insufficiency as part of their syndrome. Although there may be some increase in the complication rate, recurrence free survival seems equivalent. Some conditions require specialized approaches to adjuvant therapy, as their syndrome may make them especially susceptible to side effects.

Comprehensive bioinformatics analysis of the TP53 signaling pathway in Wilms' tumor.

BACKGROUND: Differential expression of tumor protein 53 (TP53, or p53) has been observed in multiple cancers. However, the expression levels and prognostic role of TP53 signaling pathway genes in Wilms' tumor (WT) have yet to be fully explored. METHODS: The expression levels of TP53 signaling pathway genes including TP53, mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), cyclin-dependent kinase 2A (CDKN2A), cyclin-dependent kinase 2B (CDKN2B), and tumor suppressor p53-binding protein 1 (TP53BP1) in WT were analyzed using the Oncomine database. Aberration types, co-mutations, mutation locations, signaling pathways, and the prognostic role of TP53 in WT were investigated using cBioPortal. MicroRNA (miRNA) and transcription factor (TF) targets were identified with miRTarBase, miWalk, and ChIP-X Enrichment Analysis 3 (CheA3), respectively. A protein-protein network was constructed using GeneMANIA. The expression of TP53 signaling genes were confirmed in WT samples and normal kidney tissues using the Human Protein Atlas (HPA). Cancer Therapeutics Response Portal (CTRP) was used to analyze the small molecules potentially targeting TP53. RESULTS: TP53 was significantly expressed in the Cutcliffe Renal (P=0.010), but not in the Yusenko Renal (P=0.094). Meanwhile, MDM2 was significantly overexpressed in the Yusenko Renal (P=0.058), but not in the Cutcliffe Renal (P=0.058). The expression levels of MDM4 no significant difference between the tumor and normal tissue samples. The most common TP53 alteration was missense and the proportion of TP53 pathway-related mutations was 2.3%. Co-expressed genes included ZNF609 (zinc finger protein 609), WRAP53 (WD40-encoding RNA antisense to p53), CNOT2 (CC chemokine receptor 4-negative regulator of transcription 2), and CDH13 (cadherin 13). TP53 alterations indicated poor prognosis of WT (P=1.051e-4). The regulators of the TP53 pathway included miR-485-5p and TFs NR2F2 and KDM5B. The functions of TP53 signaling pathway were signal transduction in response to DNA damage and regulate the cell cycle. The small molecules targeting TP53 included PRIMA-1, RITA, SJ-172550, and SCH-529074. CONCLUSIONS: TP53 was found to be differentially expressed in WT tissues. TP53 mutations indicated poor outcomes of WT. Therefore, pifithrin-mu, PRIMA-1, RITA, SJ-172550, and SCH-529074 could be used in combination with traditional chemotherapy to treat WT.

Wilms tumor: a review of current surgical controversies.

Overall survival (OS) for children with Wilms tumor (WT) currently stands at around 90%. This is markedly improved from the survival rates of around 30% reported in the middle of the last century. This improvement is due to the development of multimodal treatment for this disease, based on the evidence yielded through international collaboration on trials conducted by the Société Internationale d'Oncologie Pédiatrique (SIOP) and the Children's Oncology Group (COG). In this article, we review some of the current surgical controversies surrounding the management of WT.

MiR-155-5p exerts tumor-suppressing functions in Wilms tumor by targeting IGF2 via the PI3K signaling pathway.

BACKGROUND: MicroRNA-155-5p (miR-155-5p) has been reported to play an oncogenic role in different human malignancies; however, its role in Wilms tumor (WT) remains unclear. METHODS: Differentially expressed miRNAs (DE-miRNAs) and mRNAs (DEGs) in WT blood and tissues were identified by using miRNA microarray and RNA-sequencing. Bioinformatics prediction and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the potential functions of DE-miRNAs. DE-miRNAs and DEGs in WT obtained from Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were identified by using the "edgeR" package. RT-qPCR was used to explore miR-155-5p and IGF2 expression and their clinical significance in WT specimens. A rhabdoid cell line (G401) and Ewing sarcoma cell line (SK-NEP-1) were used. Immunohistochemical staining, western blotting and dual-luciferase reporter assays were performed to study the mechanisms involved. The CCK-8, flow cytometry, wound healing and transwell assays were performed to identify the effects of miR-155-5p and IGF2 knockdown on cell proliferation, apoptosis, migration and invasion, respectively. RESULTS: MiR-155-5p was downregulated in both blood and tissues from WT patients who did not receive chemotherapy before surgery but was upregulated in tissues from WT patients who had received chemotherapy before surgery. IGF2, PI3K, AKT and mTOR were found to be upregulated in WT tissues. Additionally, miR-155-5p and IGF2 were significantly correlated with TNM stage and lymphatic metastasis in WT patients. Molecular mechanism exploration indicated that IGF2 was downregulated by miR-155-5p via direct binding to its 3' untranslated region in cell lines. Furthermore, IGF2, PI3K, AKT and mTOR expression was inversely correlated with miR-155-5p expression, and PI3K, AKT and mTOR expression was positively correlated with IGF2 expression in cell culture. Functional studies demonstrated that miR-155-5p upregulation and IGF2 knockdown suppressed cell proliferation, migration and invasion and induced cell apoptosis. Moreover, the tumor-suppressing effects of miR-155-5p in cells were abrogated by miR-155-5p inhibitor treatment. CONCLUSIONS: Taken together, these findings suggest that miR-155-5p functions as a tumor suppressor in WT through inactivating the PI3K/AKT/mTOR signaling pathway by directly targeting IGF2. Thus, miR-155-5p might be a novel therapeutic target for WT.

Comprehensive analysis of competing endogenous RNA network in Wilms tumor based on the TARGET database.

BACKGROUND: Wilms tumor (WT) was the most common malignant tumor of urinary system in children. With the advances in gene sequencing, research of molecular mechanism of WT tumor was gradually increasing. However, few studies have explored the influence of competing endogenous RNA (ceRNA) in WT. Accordingly, we aimed to explore the mechanisms of ceRNA co-expression network in WT. METHODS: A total of 6 non-tumor controls and 127 WT patients' RNA-seq data combined with clinical data was acquired from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Differentially expressed lncRNA, miRNA and mRNA between WT tissues and normal tissues were analyzed using "edgeR" package in R software. Weighted gene co-expression network analysis (WGCNA) was utilized to construct the ceRNA co-expression network while Molecular Complex Detection (MCODE) algorithm was used to extract the pivotal sub-network. Function annotation of mRNA was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Survival analysis was then conducted based on long-rank test and Kaplan-Meier curves using the survival package. RESULTS: By applying the "edgeR" package in R, the transcriptome expression data of 127 WT tissues with 6 normal tissues were normalized. Moreover, 146 DElncRNAs, 62 DEmiRNAs, 287 DEmRNAs of them were involved in ceRNA network after applying WGCNA. According to MCODE, we identified that the interactions between LINC002253 (lncRNA) and TRIM71 (mRNA) was mediated by hsa-mir-301a and hsa-mir-301b (miRNA). Furthermore, we detected 13 DElncRNAs which were significantly associated with the progression of WT. CONCLUSIONS: We used WGCNA method to construct the WT ceRNA network for the first time. TRIM71 was identified to be the most closely related genes involved in hub sub-network by MCDOE, suggesting it might act as a new drug target and prognostic factor based on our comprehensive results.

MYC gene associated polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study.

BACKGROUND: Wilms tumor (WT) is a common embryonal malignancy in the kidney, ranking fourth in childhood cancer worldwide. MYC, a critical proto-oncogene, plays an important role in tumorigenesis. Single nucleotide polymorphisms in the MYC gene may lead to the deregulation of MYC proto-oncogene protein and thereby promote the initiation and development of tumors. METHODS: Here, we assessed the association between MYC gene associated polymorphisms and WT susceptibility by performing a case-control study with 355 cases and 1070 controls. Two MYC gene associated polymorphisms (rs4645943 C > T, rs2070583 A > G) were genotyped by TaqMan technique. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for evaluating the association between these two polymorphisms and WT susceptibility. RESULTS: No significant association was detected between the selected polymorphisms and WT risk in the overall analysis as well as stratification analysis. CONCLUSIONS: These results indicate that neither of two selected MYC gene associated polymorphisms might affect WT susceptibility in the Chinese population. Large well-designed studies with diverse ethnicities are warranted to verify these results.

Investigating the dysfunctional pathogenesis of Wilms' tumor through a multidimensional integration strategy.

BACKGROUND: Wilms' tumor (WT) is a common kidney tumor in early childhood which is characterized by multiple congenital anomalies and syndromes. With the continuous improvement of medical standards, the cure rate and survival period of WT have increased. However, its molecular mechanism is still elusive. METHODS: A comprehensive multidimensional integration strategy was used to comprehensively analyze the mechanisms of WT. RESULTS: By integrating the potential pathogenic genes of kidney cancer and performing co-expression analysis on the disease-related genes, 23 functional modules were obtained. All the genes were differentially expressed in WT, and were mainly involved in many biological processes and signaling pathways, such as Wnt/ß-catenin, mTOR/ERK and calcineurin. Additionally, based on the relationship between transcriptional and post-transcriptional regulatory systems, in functional modules, transcription factors (TFs) including STAT3, HDAC1 and SP1 as well as non-coding RNAs (ncRNAs) such as miR-335-5p, miR-21-5p and TUG1 were identified. Finally, potential drugs for these multifactor regulated dysfunctional modules which may have certain pharmacological or toxicological effects on WT such as cisplatin, sorafenib, and zinc were predicted. CONCLUSIONS: A multidimensional dysfunction mechanism, involving disease-related genes, TFs and ncRNAs was revealed in the pathogenesis of WT. Functional modules were used to predict potential drugs which can be used in personalized therapy and drug delivery. This study explored the pathogenesis of WT from a new perspective, and provides new candidate targets and therapeutic drugs for improving the cure rate of WT.

Immunotherapeutic Targeting of GPC3 in Pediatric Solid Embryonal Tumors.

Glypican 3 (GPC3) is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of pediatric solid embryonal tumors including the majority of hepatoblastomas, Wilms tumors, rhabdoid tumors, certain germ cell tumor subtypes, and a minority of rhabdomyosarcomas. Via both its core protein and heparan sulfate side chains, GPC3 activates the canonical Wnt/ß-catenin pathway, which is frequently overexpressed in these malignancies. Loss of function mutations in GPC3 lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor. There are several immunotherapeutic approaches to targeting GPC3, including vaccines, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, cytolytic T lymphocytes, and CAR T cells. These therapies offer a potentially novel means to target these pediatric solid embryonal tumors. A key pediatric-specific consideration of GPC3-targeted immunotherapeutics is that GPC3 can be physiologically expressed in normal tissues during the first year of life, particularly in the liver and kidney. In summary, this article reviews the current evidence for targeting childhood cancers with GPC3-directed immunotherapies.