Pediatric Renal Malignancy Research Articles

Stratification of Wilms tumor patients using physicochemical properties of the adaptive immune receptor polypeptides, IGL and TRG

Wilms tumor (WT) is the most common pediatric renal malignancy. Current guidelines that stratify WT risk and determine treatment courses are inadequate, as over 60% of WT survivors develop treatment-related complications. Recently, numerous advances in establishing patient sub-groups with different clinical features have been realized by evaluating the adaptive immune receptor (IR) complementarity determining region-3 (CDR3) amino acid (AA) sequences, a reasonable series of successes, given the prominent role of the CDR3 in antigen binding, including tumor antigen binding. However, the possibility that adaptive IR chemical variability correlates with distinct survival outcomes for WT has not yet been explored. The goal of this study was to isolate the T-cell receptor and B-cell receptor recombination, sequencing reads from WT RNAseq files, representing the actual tumor tissue, translate the sequences to AAs, identify the adaptive IR CDR3 domains, and determine whether the physicochemical properties of those CDR3 AA sequences correlated with survival probability distinctions. WT RNA-seq files were mined to obtain the CDR3 AAs for various adaptive IRs. The physicochemical properties of these CDR3s were examined for trends in how those properties correlated with survival probabilities for WT patients, using a Kaplan-Meier analyses, verified via several approaches. The above processes indicated the association of the (a) IGL CDR3s' instability index and the (b) TRG CDR3s' fraction disorder promoting features with better outcomes. Additionally, the IGL CDR3 data were assessed using the Predictor of Natural Disordered Regions web tool, which strengthened the evidence for the association with the IGL CDR3 instability index with a better outcome. The approaches described here indicate that greater adaptive IR CDR3 instability and flexibility may serve as prognostic indicators; and may indicate the flexibility of CDR3 domains provides for greater opportunity to bind tumor antigens. Further exploration and development of these approaches and findings may lead to new guidelines for more precise treatment regimens, or even watchful waiting periods, that could thereby decrease the lifetime occurrence of adverse events.

Pediatric renal malignancy diagnosis is associated with significant burden of care for families.

New childhood cancer diagnoses require timely, complex care coordination and cause considerable logistic burden for families. We used renal tumors as a model to examine healthcare utilization and cost following new solid tumor diagnosis. Children (ages 0-21) with International Classification of Disease (ICD) codes for renal malignancy and subsequent nephrectomy were identified from North Carolina Medicaid claims data (2014-2020). We stratified patients by duration of follow-up, then quantified healthcare utilization and billing totals. Eighty-one children met study criteria. Median age at diagnosis was 3years (interquartile range [IQR]: 1-5). Median family monthly earned income was $0. One month following diagnosis, children cumulatively spent a median of 16days receiving medical care (IQR: 10-20), 28days at 3months (IQR: 21-43), and 50.5days at 1year (IQR: 35-94.5). Children cumulatively spent a median 12days as inpatients during the first 3months (IQR: 7-17) and 13.5days at 1year (IQR: 8.5-37). Children cumulatively completed a median 12 outpatient encounters at 3months (IQR: 7-17) and 26 at 1year (IQR: 12-36). At 1year, median Medicaid claim reimbursements for children with renal malignancy was $50,041 (IQR: $36,670-$80,734). In examining healthcare utilization in children with renal tumor diagnoses, the substantial number of days spent in medical facilities greatly impacts the burden of care on families, especially for those with limited financial resources. Awareness of this logistic strain on families and careful planning to consolidate patient visits may improve the navigability of pediatric cancer regimens for families, particularly those with limited resources.

A Single Center Experience With Bilateral Wilms Tumor.

Wilms tumor (WT) is the most common pediatric renal malignancy and bilateral disease (BWT) occurs in 5% of cases and is associated with poor outcomes. Management of BWT includes chemotherapy and oncologic resection while preserving renal function. Previous literature has demonstrated variable approaches in BWT treatment. The aim of this study was to examine a single institution experience and outcomes with BWT. A retrospective chart review was performed for all patients with WT treated at a free-standing tertiary children's hospital between 1998 and 2018. Patients with BWT were identified and treatment courses were compared. Outcomes of interest included need for dialysis post-operatively, need for renal transplantation post-operatively, disease recurrence, and overall survival. Of 120 children with WT, 9 children (6F:3M) of median age 32months (IQR: 24-50months) and median weight 13.7kg (IQR: 10.9-16.2kg) were diagnosed with and treated for BWT. Pre-operative biopsies were obtained in 4/9 patients, 3 of whom received neoadjuvant chemotherapy and 1 who underwent radical nephrectomy. Of the 5 patients who did not undergo biopsy, 4/5 were treated with neoadjuvant chemotherapy, and 1/5 underwent upfront nephrectomy. Post-operatively, 4/9 children required dialysis, of whom 2 subsequently underwent renal transplantation. Two patients were lost to follow-up, and of the remaining 7 patients, disease recurrence occurred in 5/7 children and overall survival was 71% (n=5). Management of BWT varies regarding the use of pre-operative biopsy, neoadjuvant chemotherapy, and extent of disease resection. Further guidelines on treatment protocols may optimize outcomes in children with BWT.

Clinical relevance of BCOR internal tandem duplication and TP53 aberration in clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy, characterized by BCOR internal tandem duplication (ITD), YWHAE rearrangement, BCOR-CCNB3 fusion, and lack of other consistent structural alteration. We accidentally identified TP53 deletion in CCSK, which was often associated with adverse clinical outcomes. In this study, we assessed the incidence as well as the clinical relevance of these molecules in CCSK patients. BCOR ITD, YWHAE rearrangement, BCOR-CCNB3 fusion and TP53 status were examined by polymerase chain reaction, fluorescence in situ hybridization, or Sanger sequencing in a cohort of 39 patients with CCSK. Among them, 34 cases (87.18%) had BCOR ITD, 1 (2.56%) had YWHAE rearrangement, and 1 (2.56%) had BCOR-CCNB3 gene fusion. The remaining 3 (7.69%) harbored none of these aberrations. BCOR ITD, YWHAE rearrangement and BCOR-CCNB3 were mutually exclusive. Furthermore, 25.64% of the cohort acquired TP53 aberration (10/39, 3 with both copy number deletion and point mutation, 6 with deletion only, and 1 with mutation only), all of which were associated with BCOR ITD. Patients with or without BCOR ITD or TP53 aberration did not differ in demographic characteristics such as sex, onset age, or tumor stage at diagnosis. However, the overall survival rates and progression-free survival rates of BCOR ITD or TP53 deletion groups showed obvious downward trends, albeit not all reaching statistical significance. Patients with both BCOR ITD and TP53 deletion had the poorest prognosis.

A Nomogram-Based Risk Classification System Predicting the Overall Survival of Childhood with Clear Cell Sarcoma of the Kidney Based on the SEER Database.

Objective Clear cell sarcoma of the kidney (CCSK) is a lethal pediatric renal malignancy with poor prognosis. A prognostic nomogram needs to be established for overall survival (OS) prediction of patients with CCSK. Methods Eligible 2588 CCSK patients (age 0–19) diagnosed between 2000 and 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomized into training and validation cohorts (7 : 3). Independent prognostic factors were identified by univariate and multifactorial Cox regression analyses and used to construct a nomogram. Receiver operating characteristics (ROC) analysis, calibration curves, and decision curve analysis (DCA) were used to validate the nomogram. Moreover, a risk classification system was established based on the risk scores of the nomogram. Results Cox analyses revealed that age, combined stage, and origin were most significant prognostic factors. Based on these prognostic factors, a nomogram was established for predicting 3- and 5-year OS of patients with CCSK. The area under the ROC curve (AUC) of 3- and 5-year OS was 0.733 and 0.728 in the training cohort, corresponding to 0.69 and 0.674 in the validation cohort. The C-index of calibration curves in the training and validation cohorts was 0.724 and 0.686. DCAs indicated the clinical utility of this nomogram. A risk classification system stratified CCSK patients into three different risk cohorts. The OS time of low-, intermediate-, and high-risk patients was 76, 68, and 65 months in the training cohort, corresponding to 69.5, 66, and 72 months in the validation cohort. Conclusion A nomogram-based risk classification system has high accuracy for the prognostic prediction of CCSK.

PDGF-BB/PDGFRβ promotes epithelial-mesenchymal transition by affecting PI3K/AKT/mTOR-driven aerobic glycolysis in Wilms' tumor G401 cells.

Wilms' tumor (WT) is the most common pediatric renal malignancy. PDGFRβ belongs to the type III receptor tyrosine kinase family and is known to be involved in tumor metastasis and angiogenesis. Here, we studied the effect and underlying mechanism of PDGFRβ on WT G401 cells. Transwell assay and wound-healing assay were used to detect the effect of PDGFRβ on G401 cells invasion and migration. Western blot and immunofluorescence were used to detect the expression of EMT-related genes. The expression of PI3K/AKT/mTOR pathway proteins was detected by Western blot. The relationship between PDGFRβ and aerobic glycolysis was studied by assessing the expression of glycolysis-related enzymes detected by qRT-PCR and Western blot. The activity of HK, PK, and LDH was detected by corresponding enzyme activity kits. The concentration of lactic acid and glucose was detected by Lactic Acid Assay Kit and Glucose Assay Kit-glucose oxidase method separately. To investigate the mechanism of PDGFRβ in the development of WT, the changes of glucose and lactic acid were analyzed after blocking PI3K pathway, aerobic glycolysis, or PDGFRβ. The key enzyme was screened by Western blot and glucose metabolism experiment after HK2, PKM2, and PDK1 were inhibited. The results showed that PDGFRβ promoted the EMT process by modulating aerobic glycolysis through PI3K/AKT/mTOR pathway in which PKM2 plays a key role. Therefore, our study of the mechanism of PDGFRβ in G401 cells provides a new target for the treatment of WT.

Role of Cyclin D1 and BCOR Immunohistochemistry in Differentiating Clear Cell Sarcoma of Kidney From its Mimics.

Clear cell sarcoma of kidney (CCSK) is the second most common pediatric renal malignancy, constituting ∼3% of renal tumors. Due to its morphologic diversity, the diagnosis of CCSK is often challenging. Recent studies have identified internal tandem duplication of BCL6 corepressor (BCOR) gene in CCSKs which coupled with cyclin D1 immunoreactivity, is helpful in differentiating it from its mimics, particularly blastema-rich Wilms tumor (WT), malignant rhabdoid tumor (MRT), and congenital mesoblastic nephroma (CMN). We aimed to evaluate the utility of cyclin D1 and BCOR immunohistochemistry in differentiating CCSK from its morphologic mimics. Our cohort comprised of 38 pediatric renal tumors which included CCSK (n=18), WT (n=10), MRT (n=5), and CMN (n=5) cases. A detailed clinicopathologic analysis was performed, and tissue microarray were constructed for CCSK and WT, while MRT and CMN tumors were individually stained. The age ranged from 2 months to 16 years with male:female ratio of 3:1. Strong, diffuse nuclear immunoreactivity for cyclin D1 and BCOR was noted in 61% (n=11/18) and 83% (n=15/18) of CCSK, respectively, while it was significantly less in WT (n=3/10 for cyclin D1) (n=2/10 for BCOR). None of the MRT and CMN examples demonstrated any immunoreactivity. Interestingly, only the blastemal component of WTs showed distinct, rare nuclear immunoreactivity for cyclin D1 or BCOR and the combination of these was never positive in a given case. Our results provide evidence that concurrent immunopositivity with cyclin D1 and BCOR is helpful in distinguishing CCSK from its morphologic mimics.

Abstract 98: Custom Gene Fusion Assays for the Rapid Diagnosis of Pediatric Cancers in Low-Resourced Settings

Abstract Purpose: Risk stratification and molecular targeting have been key to increasing cure rates for pediatric cancers in high-income countries. Precise diagnosis and successful treatment of pediatric cancer in low-resourced settings is often hindered by insufficient pathology infrastructure, including lack of laboratory platforms for molecular analysis. Given the high frequency of gene fusions in pediatric cancers, identifying such fusions would greatly aid cost-effective pediatric cancer diagnosis, risk stratification, and precision medicine in low-resourced settings. Methods: To allow for implementation of gene fusion detection at Global HOPE sites in Sub-Saharan Africa (SSA), methodologies were reviewed to consider minimal technical expertise required, the ability to utilize samples with sub-optimal RNA quality, and rapid turn-around-time. Literature review, clinical laboratory results, public databases, and large-scale genomic studies were used to obtain exact breakpoint sequence information for gene fusions associated with pediatric and adolescent cancers. Results: Two custom pediatric gene fusions panels were designed using the NanoString Elements technology. The hematologic malignancy panel was designed to detect 439 breakpoints for 223 non-IGH/TCR fusions reported in ALL, AML, lymphomas, and histiocytosis. The solid tumor panel was designed to detect 204 breakpoints for 436 fusions associated with pediatric sarcomas, brain tumors, and renal malignancies. Each panel was tested using 96 samples with known fusion status at Texas Children's Hospital to determine specificity, sensitivity, precision, and ease of workflow. Conclusions: The design, testing, and implementation of a rapid assay to detect gene fusions with diagnostic, prognostic, and therapeutic impact would be transformational in the care of pediatric cancer patients in low-resourced settings. The custom designed panels will allow for large-scale fusion detection in 2-3 days with only 15 minutes of technician time after RNA isolation. Additional steps are needed to identify and address any challenges upon initiation in SSA to fully realize the potential of such technology. Citation Format: Julie Gastier-Foster, Fredrick Lutwama, Joseph Lubega, Kevin Fisher, Dolores Lopez-Terrada, Angshumoy Roy, Nmazuo Ozuah, Jeremy Slone, Peter Wasswa, Carl Allen, David Poplack. Custom Gene Fusion Assays for the Rapid Diagnosis of Pediatric Cancers in Low-Resourced Settings [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 98.

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.

Progress Update in Pediatric Renal Tumors.

Pediatric renal tumors account for 7% of new cancer diagnoses in children. Here, we will review results from recently completed clinical trials informing the current standard of care and discuss targeted and immune therapies being explored for the treatment of high risk or relapsed/refractory pediatric renal malignancies. Cooperative group trials have continued to make improvements in the care of children with pediatric tumors. In particular, trials that standardize treatment of rare cancers (e.g., bilateral Wilms tumor) have improved outcomes significantly. We have seen improvements in event free and overall survival in recently completed clinical trials for many pediatric renal tumors. Still, there are subsets of rarer cancers where outcomes remain poor and new therapeutic strategies are needed. Future trials aim to balance treatment toxicity with treatment efficacy for those with excellent outcomes while identifying novel therapeutics for those with poor outcomes.

Wilms' Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages.

Simple SummaryWilms’ tumor (WT) is the most common childhood renal tumor accounting for approximately 7% of childhood malignancies. The overall survival rate for patients with favorable histology is greater than 90% while the survival rate for patients with poor prognostic factors is around 50%. The current treatments consist in a combination of surgery and chemotherapy or radiotherapy in high risk patients. Such treatments are responsible for significant adverse effects requiring long-term monitoring. Thus, a main challenge in WT treatment is the development of novel therapeutic strategies to eliminate or minimize the adverse effects. The characterization of an immune environment could allow the identification of new therapeutic targets. Herein we studied the interaction between WT and innate immune cells, in particular NK cells and monocytes. Although WT are highly susceptible to NK-mediated lysis, the detection of immunoregulatory activity of WT tumor cells on NK cells and also on monocytes could offer novel cellular and molecular targets for an efficacious immunotherapy of WT.The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56+/CD133−) or an epithelial (CD56−/CD133+) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.

The contribution of WTAP gene variants to Wilms tumor susceptibility.

Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI=0.61-0.995, P=0.046). Single locus analysis of rs9457712 G>A and rs7766006 G>T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.

Methylation Statuses of H19DMR and KvDMR at WT2 in Wilms Tumors in Taiwan.

Wilms tumor is the most common pediatric renal malignancy. Several genetic loci have been shown to be associated with its formation. Genetic or epigenetic aberrations at WT1 and WT2 loci have been implicated in the etiology of the majority of sporadic Wilms tumors. In our previous study, most Wilms tumors tested negative for both constitutional mutations and somatic mutations in the WT1 gene. Thus, WT2 may play an important role in these tumors. In the present study, we analyzed the methylation statuses of WT2 at 11p15 using methylation sensitive multiplex ligation-dependent probe amplification in six Wilms tumors. Paternal uniparental disomy at WT2 was observed in two Wilms tumors with epithelial components due to hypermethylation at H19DMR and hypomethylation at KvDMR. Our findings highlight the benefits of testing for 11p15 epigenetic abnormalities to identify Wilms tumors with epithelial components.

Diagnostic Utility of BCOR Antibody in Clear Cell Sarcomas of Kidney.

Purpose. Clear cell sarcoma of the kidney (CCSK) is an uncommon malignant renal tumor. It is the second most common renal pediatric renal malignancy after Wilms tumor. It exhibits a heterogeneous morphology, with overlapping features with its close differentials, which results in diagnostic challenges. There was no specific immunohistochemical marker in the past, to help in this regard. BCOR antibody has recently been suggested to be helpful in the differential diagnosis. We aim to study the utility of the BCOR antibody in the diagnosis of CCSK. Methods. We selected a total of 27 cases of CCSK (n = 12), Wilms tumor (n = 12), and congenital mesoblastic nephroma (n = 3). All cases were evaluated for the extent and intensity of nuclear labeling for BCOR antibody by immunohistochemistry (IHC). Results. We found that BCOR IHC was positive in 11 out of 12 cases with diffuse and strong staining in 8 of the cases. None of the cases of Wilms tumor and congenital mesoblastic nephroma were positive. Only 2 cases of Wilms tumor showed minimal and weak staining in <5% of cells. Conclusion. Diffuse and strong nuclear staining for the BCOR antibody is highly specific for CCSK among common pediatric renal malignancies. Our study confirms that BCOR IHC is a good IHC marker for the diagnosis of CCSK.

Lessons learned from the developmental origins of childhood renal cancer.

Despite the rarity of renal tumors in children, many different types of malignant and nonmalignant renal neoplasms have been described. Therefore, the correct diagnosis and clinical management of these patients can represent a challenge. Here we provide a comprehensive review of the commonly diagnosed pediatric renal malignancies, including nephroblastoma (commonly known as Wilms tumor), clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, several subtypes of renal cell tumors (often collectively termed renal cell carcinoma), and congenital mesoblastic nephroma. The epidemiology, pathology, treatments, underlying genetic and molecular mechanisms, and proposed developmental origins are discussed in detail, highlighting differential features and potential improved therapeutic strategies for affected individuals.

MicroRNA-483-3p Promotes Proliferation, Migration, and Invasion and Induces Chemoresistance of Wilms' Tumor Cells.

Wilms' tumor is the most common pediatric renal malignancy. MiRNAs are important regulators in multiple cancers including Wilms' tumor. In this study, we examined the role of miR-483-3p on proliferation, chemosensitivity, migration, and invasion of Wilms' tumor cells. The proliferation of Wilms' tumor cells was examined using WST-1 assay. The migration and invasion of Wilms' tumor cells were evaluated by transwell migration assay and matrigel invasion assay. The protein expression levels were detected by Western blot. The effect of miR-483-3p on doxorubicin-induced apoptosis in Wilms' tumor cells was evaluated by caspase-Glo3/7 assay. Forced expression of miR-483-3p promoted the proliferation, migration, and invasion in Wilms' tumor cells. Meanwhile, miR-483-3p decreased the sensitivity of Wilms' tumor cells after doxorubicin treatment. MiR-483-3p inhibited the doxorubicin-induced apoptosis in Wilms' tumor cells by the regulation of BAX and Bcl-2 expression. Furthermore, miR-483-3p regulated epithelial-mesenchymal transition by affecting the expression of E-cadherin, N-cadherin, snail, and vimentin in Wilms' tumor cells. Further studies showed that the expression levels of PTEN and p-AKT in Wilms' tumor cells were changed after aberrant expression of miR-483-3p by binding to 3'-UTR of PTEN. Our study suggests that miR-483-3p played important roles in proliferation and progression in Wilms' tumor cells and might serve as a potential prognostic biomarker and predict chemotherapy response in Wilms' tumor.

Potential Five-MicroRNA Signature Model for the Prediction of Prognosis in Patients with Wilms Tumor.

BackgroundWilms tumor (WT) is the most common type of pediatric renal malignancy, and is associated with poor prognosis. The aim of the present study was to identify microRNA (miRNA) signatures which might predict prognosis and categorize WTs into high- and low-risk subgroups.Material/MethodsThe miRNA expression profiles of WT patients and normal samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment database. Differentially expressed miRNAs between WT patients and normal samples were identified using the EdgeR package. Subsequently, correlations between differentially expressed miRNAs and the prognosis of overall survival were analyzed. Enrichment analyses for the targeted mRNAs were conducted via the Database for Annotation, Visualization, and Integration Discovery.ResultsA total of 154 miRNAs were identified as differentially expressed in WT. Of those, 18 miRNAs were associated with overall survival (P<0.05). A prognostic signature of 5 differentially expressed miRNAs (i.e., has-mir-149, has-mir-7112, has-mir-940, has-mir-1248, and has-mir-490) was constructed to classify the patients into high- and low-risk subgroups. The targeted mRNAs of these prognostic miRNAs were primarily enriched in Gene Ontology terms (i.e., protein autophosphorylation, protein dephosphorylation, and stress-activated MAPK cascade) and the Kyoto Encyclopedia of Genes and Genomes signaling pathways (i.e., MAPK, AMPK, and PI3K-Akt).ConclusionsThe 5-miRNA signature model might be useful in determining the prognosis of WT patients. As a promising prediction tool, this prognosis signature might serve as a potential biomarker for WT patients.

Investigation of association between LINC00673 rs11655237 C>T and Wilms tumor susceptibility.

BackgroundWilms tumor (WT) is the most common pediatric renal malignancy. Previous genome‐wide association studies have identified that the LINC00673 rs11655237 C>T polymorphism is associated with the risk of several types of cancer. However, few studies have investigated the association between LINC00673 rs11655237 C>T and WT susceptibility.MethodWe genotyped LINC00673 rs11655237 C>T in 145 patients with WT and 531 cancer‐free controls recruited from southern Chinese children. The strength of association was estimated by odds ratios (ORs) and 95% confidence intervals (CIs).ResultsOur study indicated that there was no significant association between LINC00673 rs11655237 C>T polymorphism and WT risk under all the tested genetic models (CT vs CC: adjusted OR = 0.94, 95% CI = 0.63‐1.40; TT vs CC: adjusted OR = 0.60, 95% CI = 0.22‐1.59; TT/CT vs CC: adjusted OR = 0.89, 95% CI = 0.61‐1.31; and TT vs CC/CT: adjusted OR = 0.61, 95% CI = 0.23‐1.61). Further stratified analysis detected no significant association, either.ConclusionIn conclusion, we failed to find any association between the LINC00673 rs11655237 C>T polymorphism and WT risk. This finding needs to be verified in larger studies and other populations.

Correlations between Histological and Array Comparative Genomic Hybridization Characterizations of Wilms Tumor.

Wilms tumor, or nephroblastoma, is the most common pediatric renal malignancy. Its diagnosis is principally based on histology. Several genetic loci have been shown to be associated with Wilms tumor formation, including WT1, WT2, FWT1, FWT2, CTNNB1, WTX, and TP53. Other loci, such as 1p, 2q, 7p, 9q, 12q, 14q, 16q, 17p, and 22, have also been implicated in the etiology of Wilms tumor. The aim of this study is to elucidate the molecular pathogenesis of this tumor. In the present study, we analyzed the histological appearance and copy number aberrations using array comparative genomic hybridization of six Wilms tumors without somatic mutation in the WT1 gene. Many chromosomal aberrations on array comparative genomic hybridization analysis revealed that the genetics of Wilms tumors are extremely complex. Amplifications and deletions of large DNA fragments were observed in some samples. Amplifications of NDUFV1, ZIC2, SIX1, NR2F2, MIR1469, SOX9, JAG1, MIR6870, and GNAS were found in all six Wilms tumors. Moreover, amplifications of five genes were identified in the Wilms tumors of stromal type and amplifications of at least 10 genes were identified in the Wilms tumors of epithelial type. Our results indicated that amplifications of nine genes are the essential events in the tumorigenesis of Wilms tumor, which may inform its clinical and therapeutic management. In addition, mixed type Wilms tumor may be the heterogeneous group able to be classified using genetic results of epithelial and stromal components based on immunohistochemistry.

Clinical outcomes of children with Wilms tumor treated on a SIOP WT 2001 protocol in a tertiary care hospital in south India

Wilms tumor is the most common pediatric renal malignancy. While developed countries have had excellent survival, it remains poorer by comparison in developing countries. The aim was to analyze the clinical outcome of children with Wilms tumor managed in a developing country from 2004 to 2014 by the SIOP WT 2001 protocol. Fifty-nine children with Wilms tumor managed by a SIOP WT 2001 regimen from 2004 to 2014 were analyzed. The median age at presentation was 36 months, and 59% were boys. The average size of the tumor at presentation was 523mL. Inferior vena cava thrombus was present in 11, distant metastases in 18, and bilateral tumors in six. Preoperative chemotherapy was given to all children after a diagnostic core needle biopsy. Preoperative chemotherapy reduced the tumor size to a mean of 208mL and resolved venacaval thrombus in eight. Fifty-five children underwent definitive surgery while two children died during preoperative chemotherapy and two remained inoperable. All surviving children received adjuvant chemotherapy with 17 receiving radiotherapy as well. The overall survival (OS) was 80% and the event-free survival (EFS) was 73% after a mean follow up of 42 months after completion of therapy. The tumor volumes at presentation and the incidence of venous tumor thrombosis in our cohort were much higher than those reported from developed countries. The incidence of metastatic disease at diagnosis (30.5%) was significantly higher than the 10-12% reported in Western data, but similar to that reported from various developing countries (14.1-31%). The OS in our cohort was 80% and the EFS was 73% with there being no events after 28 months. Although the survival rate for localized disease is similar to that in developed countries, the OS for metastatic disease was significantly less (50% vs. 75%). We also found that using an upfront posterior flank core biopsy was safe and beneficial for differentiating Wilms tumor from other pediatric renal tumors that are less chemosensitive. In a resource-restricted environment such as ours, the SIOP WT 2001 protocol has been found to show excellent results.