RESUMEN
OBJECTIVE: To identify the key genes differentially expressed in Wilms tumor and analyze their potential impacts on prognosis and immune responses of the patients. METHODS: High-throughput RNA sequencing was used to identify the differentially expressed mRNAs in clinical samples of Wilms tumor and paired normal tissues, and their biological functions were analyzed using GO, KEGG and GSEA enrichment analyses. The hub genes were identified using STRING database, based on which a prognostic model was constructed using LASSO regression. The mutations of the key hub genes were analyzed and their impacts on immunotherapy efficacy was predicted using the cBioPortal platform. RT-qPCR was used to verify the differential expressions of the key hub genes in Wilms tumor. RESULTS: Of the 1612 differentially expressed genes identified in Wilms tumor, 1030 were up-regulated and 582 were down-regulated, involving mainly cell cycle processes and immune responses. Ten hub genes were identified, among which 4 genes (TP53, MED1, CCNB1 and EGF) were closely related to the survival of children with Wilms tumor. A 3-gene prognostic signature was constructed through LASSO regression analysis, and the patients stratified into with high- and low-risk groups based on this signature had significantly different survival outcomes (HR=1.814, log-rank P=0.002). The AUCs of the 3-, 5- and 7-year survival ROC curves of this model were all greater than 0.7. The overall mutations in the key hub genes or the individual mutations in TP53/CCNB1 were strongly correlated with a lower survival rates, and a high TP53 expression was correlated with a poor immunotherapy efficacy. RT-qPCR confirmed that the key hub genes had significant differential expressions in Wilms tumor tissues and cells. CONCLUSION: TP53 gene plays an important role in the Wilms tumor and may potentially serve as a new immunotherapeutic biomarker as well as a therapeutic target.
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Neoplasias Renales , Tumor de Wilms , Humanos , Tumor de Wilms/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Pronóstico , Neoplasias Renales/genética , Genes del Tumor de Wilms , Microambiente TumoralRESUMEN
OBJECTIVE: This study aimed to investigate the role and mechanism of microRNA (miR)-193a in promoting apoptosis of retinal neuronal cells in early diabetic (DM) rats. METHODS: Seventy-two male SD-grade rats were selected to establish a DM model by intraperitoneal injection of streptozotocin (STZ), and randomly divided into a control group (blank control group), a DM group (diabetic model group), a DM+miR-NC inhibitor group (miR-193a inhibition negative control group), a DM+miR-193a inhibitor group (miR-193a inhibitor group), DM+miR-NC mimic group (miR-193a overexpression negative control group), DM+miR-193a mimic group (miR-193a overexpression group), with12 rats in each group. RESULTS: The miR-193a expression, apoptosis rate, and Bax, Caspase3, and Caspase9 protein expression levels were elevated, and Bcl-2 protein expression was decreased in the retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells, while miR-193a inhibitors reversed these processes. These dual luciferase reporter assay showed that WT1CDS, and WT1Mut were lower in the miR-193a group than in the miR-NC group (P<0.05); WT1 protein expression was reduced in the retinal tissues of DM rat and high glucose-induced rat retinal neuronal cells, and miR-193a inhibitors increased WT1 protein expression. Compared with cells co-transfected with miR-193a and WT1vector, miR-193a and WT1 cotransfection inhibited high glucose-induced apoptosis in retinal neuronal cells and regulated apoptotic protein expression. miR-193a was highly expressed and WT1 was lowly expressed in retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells. CONCLUSION: miR-193a could inhibit early retinal neuronal cell apoptosis in DM rats by targeting and negatively regulating WT1 expression.
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Apoptosis , Diabetes Mellitus , MicroARNs , Neuronas Retinianas , Animales , Masculino , Ratas , Apoptosis/genética , Genes del Tumor de Wilms , Glucosa , MicroARNs/genética , Proteínas WT1 , Neuronas Retinianas/metabolismoRESUMEN
In 1990, mutations of the Wilms' tumor-1 gene (WT1), encoding a transcription factor in the embryonic kidney, were found in 10-15% of Wilms' tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. For more than three decades, these discoveries prompted investigators to explore the embryonic role of WT1 and the mechanisms by which loss of WT1 leads to malignant transformation. Here, we discuss how alternative splicing of WT1 generates isoforms that act in a context-specific manner to activate or repress target gene transcription. WT1 also regulates posttranscriptional regulation, alters the epigenetic landscape, and activates miRNA expression. WT1 functions at multiple stages of kidney development, including the transition from resting stem cells to committed nephron progenitor, which it primes to respond to WNT9b signals from the ureteric bud. WT1 then drives nephrogenesis by activating WNT4 expression and directing the development of glomerular podocytes. We review the WT1 mutations that account for Denys-Drash syndrome, Frasier syndrome, and WAGR syndrome. Although the WT1 story began with Wilms' tumors, an understanding of the pathways that link aberrant kidney development to malignant transformation still has some important gaps. Loss of WT1 in nephrogenic rests may leave these premalignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. Yet none of these observations provide a complete picture of Wilms' tumor pathogenesis. It appears that the WT1 odyssey is unfinished and still holds a great deal of untilled ground to be explored.
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Neoplasias Renales , Tumor de Wilms , Humanos , Genes del Tumor de Wilms , Proteínas WT1/genética , Proteínas WT1/metabolismo , Riñón/metabolismo , Tumor de Wilms/genética , Tumor de Wilms/metabolismo , Mutación , Neoplasias Renales/genética , Neoplasias Renales/metabolismoRESUMEN
BACKGROUND : Nephropathy in Denys-Drash syndrome (DDS) develops within a few months of birth, often progressing to kidney failure. Wilms tumors also develop at an early age with a high rate of incidence. When a patient does not have Wilms tumor but develops kidney failure, prophylactic bilateral nephrectomy, and kidney transplantation (KTX) is an optimal approach owing to the high risk of Wilms tumor development. In the case presented here, prophylactic bilateral nephrectomy and KTX were performed in a patient who had not developed Wilms tumor or kidney failure. However, the treatment option is controversial as it involves the removal of a tumor-free kidney and performing KTX in the absence of kidney failure. CASE DIAGNOSIS/TREATMENT: We present the case of a 7-year-old boy, born at 38 weeks gestation. Examinations at the age of 1 year revealed severe proteinuria and abnormal internal and external genitalia. Genetic testing identified a missense mutation in exon 9 of the WT1 gene, leading to the diagnosis of DDS. At the age of 6 years, he had not yet developed Wilms tumor and had grown to a size that allowed him to safely undergo a KTX. His kidney function was slowly deteriorating (chronic kidney disease (CKD) stage 3), but he had not yet developed kidney failure. Two treatment options were considered for this patient: observation until the development of kidney failure or prophylactic bilateral nephrectomy with KTX to avoid Wilms tumor development. After a detailed explanation of options to the patient and family, they decided to proceed with prophylactic bilateral nephrectomy and KTX. At the latest follow-up 4 months after KTX, the patient's kidney functioned well without proteinuria. CONCLUSION: We performed prophylactic bilateral nephrectomy with KTX on a DDS patient who had not developed kidney failure or Wilms tumor by the age of 7 years. Although the risk of development of Wilms tumor in such a patient is unclear, this treatment may be an optimal approach for patients who are physically able to undergo KTX, considering the potentially lethal nature of Wilms tumor in CKD patients.
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Síndrome de Denys-Drash , Neoplasias Renales , Trasplante de Riñón , Insuficiencia Renal Crónica , Insuficiencia Renal , Tumor de Wilms , Masculino , Humanos , Niño , Síndrome de Denys-Drash/complicaciones , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/cirugía , Trasplante de Riñón/efectos adversos , Tumor de Wilms/complicaciones , Tumor de Wilms/cirugía , Tumor de Wilms/genética , Genes del Tumor de Wilms , Insuficiencia Renal/genética , Nefrectomía/efectos adversos , Neoplasias Renales/complicaciones , Neoplasias Renales/cirugía , Neoplasias Renales/genética , Insuficiencia Renal Crónica/genética , Proteinuria/genética , Proteínas WT1/genéticaRESUMEN
BACKGROUND: Wilms' tumour gene 1 (WT1) is clearly recognized as a tumour promoter in diversiform of human malignancies. Nevertheless, knowledge of its expression, functions and potential molecular mechanisms in non-small cell lung cancer (NSCLC) remains elusive. METHODS: Differential expression of WT1 mRNA and protein between NSCLC and normal tissues were assessed by analyzing RNA-seq data from Oncomine and protein data from Human Protein Atlas, respectively. Subsequently, prognosis significance and immune cell infiltration were analyzed by Kaplan-Meier plotter and CIBERSORT. 60 pairs of local NSCLC tissues were involved to validate WT1 expression by quantitative PCR (qPCR) and Western blot. Moreover, Cell Counting Kit-8 (CCK-8), colony formation, transwell, dual luciferase reporter assays and in vivo xenograft tumour growth experiments were conducted to explore the function and mechanism of WT1 in NSCLC. RESULTS: Our solid data indicated that WT1 was increased in NSCLC tissues and cell lines in comparison with their matched controls. In particular, its upregulation correlated with worse prognosis and immune infiltration of the patients. Functional assays demonstrated that knockdown of WT1 inhibited NSCLC malignancy, including inhibiting cell proliferation, survival and invasion. Further exploration discovered that microRNA-498-5p (miR-498-5p) was the upstream suppressor of WT1 by directly targeting the 3' untranslated region (UTR) of WT1 mRNA. Moreover, expression of miR-498-5p was notably decreased and inversely correlated with WT1 in NSCLC tissues. Finally, we proved that miR-498-5p was a potent tumour suppressor in NSCLC by suppressing cell proliferation, survival and invasion, while WT1 restoration could in turn disrupt this suppression both in vitro and in vivo. CONCLUSION: The abnormal increase in WT1 contributes to the malignant properties of NSCLC cells, and miR-498-5p is a natural inhibitor of WT1. Our findings might facilitate the development of novel therapeutic strategies against NSCLC in the future.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes del Tumor de Wilms , Neoplasias Pulmonares/genética , Carcinógenos , Regiones no Traducidas 3' , MicroARNs/genética , Proteínas WT1/genéticaRESUMEN
Wilms' tumor gene 1 (WT1) is a transcription and post-translational factor that has a crucial role in the biological and pathological processes of several human malignancies. For hematological malignancies, WT1 overexpression or mutation has been found in leukemia and myelodysplastic syndrome. About 70-90% of acute myeloid leukemia patients showed WT1 overexpression, and 6-15% of patients carried WT1 mutations. WT1 has been widely regarded as a marker for monitoring minimal residual disease in acute myeloid leukemia. Many researchers were interested in developing WT1 targeting therapy. In this review, we summarized biological and pathological functions, correlation with other genes and clinical features, prognosis value and targeting therapy of WT1 in hematological features.
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Neoplasias Hematológicas , Leucemia , Síndromes Mielodisplásicos , Humanos , Genes del Tumor de Wilms , Neoplasias Hematológicas/genética , MutaciónRESUMEN
Wilms tumor gene 1 (WT-1 gene) is overexpressed in most patients with acute myeloid leukemia (AML) and is an indicator for minimal residual disease (MRD) monitoring, but because the WT-1 gene has relatively low specificity, further studies of the prognostic value of a combination of the WT-1 and other genes are needed. The aim of this study was to explore the prognostic value of the WT-1 gene combined with recurrent cytogenetic genes in AML. In AML, the transcript expression of the WT-1 gene was closely related to leukemic tumor burden and acted as an accurate molecular indicator for MRD detection. Most patients with low expression levels of the WT-1 gene after induction and consolidation therapy were significantly associated with favorable relapse-free survival (RFS) and overall survival (OS), but 17.6% of patients relapsed and died of primary disease. However, when analyzing the WT-1 gene combined with recurrent cytogenetic genes, none of the patients with low expression levels of the WT-1 gene and recurrent cytogenetic genes negative relapsed and died in the median follow-up time of 19 months (range: 3-94 months). Thus, the combination of the WT-1 gene and recurrent cytogenetic genes is a more accurate indicator for MRD monitoring and prognosis evaluation in AML patients.
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Genes del Tumor de Wilms , Leucemia Mieloide Aguda , Humanos , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Recurrencia , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/patología , Análisis CitogenéticoRESUMEN
In order to get a better insight into the timing of WT1 mutant Wilms tumor development, we compared the gene expression profiles of nine established WT1 mutant Wilms tumor cell lines with published data from different kidney cell types during development. Publications describing genes expressed in nephrogenic precursor cells, ureteric bud cells, more mature nephrogenic epithelial cells and interstitial cell types were used. These studies uncovered that the WT1 mutant Wilms tumor cells lines express genes from the earliest nephrogenic progenitor cells, as well as from more differentiated nephron cells with the highest expression from the stromal/interstitial compartment. The expression of genes from all cell compartments points to an early developmental origin of the tumor in a common stem cell. Although variability of the expression of specific genes was evident between the cell lines the overall expression pattern was very similar. This is likely dependent on their different genetic backgrounds with distinct WT1 mutations and the absence/presence of mutant CTNNB1.
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Neoplasias Renales , Tumor de Wilms , Humanos , Proteínas WT1/genética , Tumor de Wilms/patología , Riñón/patología , Neoplasias Renales/patología , Células Madre/metabolismo , Línea Celular Tumoral , Células Epiteliales/metabolismo , Expresión Génica , Genes del Tumor de WilmsRESUMEN
Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.
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Neoplasias Renales , Tumor de Wilms , Niño , Humanos , Genes del Tumor de Wilms , Síndrome , Tumor de Wilms/patología , Neoplasias Renales/patología , Genotipo , Susceptibilidad a EnfermedadesAsunto(s)
Neoplasias Renales , Leucemia Mieloide Aguda , Tumor de Wilms , Humanos , Pronóstico , Genes del Tumor de Wilms , Tumor de Wilms/genética , Tumor de Wilms/patología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasias Renales/genética , Neoplasias Renales/patologíaRESUMEN
Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response.
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Neoplasias Renales , Tumor de Wilms , Niño , Genes del Tumor de Wilms , Proteínas de Homeodominio/genética , Humanos , Neoplasias Renales/genética , Proteína Proto-Oncogénica N-Myc/genética , Recurrencia Local de Neoplasia/genética , Tumor de Wilms/genéticaRESUMEN
OBJECTIVES: Wilm's Tumor (WT) is the most common pediatric kidney cancer. Whereas most WTs are isolated, approximately 5% are associated with syndromes such as Denys-Drash (DDS), characterized by early onset nephropathy, disorders of sex development and predisposition to WT. CASE PRESENTATION: A 46,XY patient presenting with bilateral WT and genital ambiguity without nephropathy was heterozygous for the novel c.851_854dup variant in WT1 gene sequence. This variant affects the protein generating the frameshift p.(Ser285Argfs*14) that disrupts a nuclear localization signal (NLS) region. CONCLUSIONS: This molecular finding is compatible with the severe scenario regarding the Wilm's tumor presented by the patient even though nephropathy was absent.
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Síndrome de Denys-Drash , Neoplasias Renales , Tumor de Wilms , Niño , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patología , Genes del Tumor de Wilms , Heterocigoto , Humanos , Neoplasias Renales/genética , Proteínas WT1/genética , Tumor de Wilms/genéticaRESUMEN
Wilms' tumor 1 (Wt1) encodes a zinc finger nuclear transcription factor which is mutated in 15-20% of Wilms' tumor, a pediatric kidney tumor. Wt1 has been found to be involved in the development of many organs. In gonads, Wt1 is expressed in genital ridge somatic cells before sex determination, and its expression is maintained in Sertoli cells and granulosa cells after sex determination. It has been demonstrated that Wt1 is required for the survival of the genital ridge cells. Homozygous mutation of Wt1 causes gonad agenesis. Recent studies find that Wt1 plays important roles in lineage specification and maintenance of gonad somatic cells. In this review, we will summarize the recent research works about Wt1 in gonadal somatic cell differentiation.
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Diferenciación Celular , Gónadas , Proteínas WT1 , Animales , Femenino , Genes del Tumor de Wilms , Gónadas/crecimiento & desarrollo , Humanos , Masculino , Ratones , Proteínas WT1/genética , Proteínas WT1/fisiologíaRESUMEN
BACKGROUND: Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome. METHODS: The clinical and genetic data from 3 individuals are reported. RESULTS: This report describes the kidney manifestations in 3 individuals from 2 unrelated families with Frasier syndrome intronic WT1 mutations, noting that 2 of the 3 individuals have histologically confirmed membranoproliferative glomerulonephritis. CONCLUSIONS: These case reports support expansion of the clinical spectrum of the kidney phenotypes associated with Frasier syndrome providing evidence of an association between WT1 mutation and an immune complex-related membranoproliferative glomerulonephritis. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Síndrome de Denys-Drash , Glomerulonefritis Membranoproliferativa , Disgenesia Gonadal , Neoplasias Renales , Tumor de Wilms , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patología , Síndrome de Frasier/genética , Genes del Tumor de Wilms , Glomerulonefritis Membranoproliferativa/genética , Disgenesia Gonadal/genética , Humanos , Neoplasias Renales/genética , Mutación , Proteínas WT1/genética , Tumor de Wilms/genéticaRESUMEN
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous tetrapeptide with potential antifibrotic effect. However, the underlying mechanism in the anti-fibrosis is still unclear. Here, we try to investigate its biofunction and deeplying mechanism in liver fibrosis. Rats were administrated with carbon tetrachloride (CCl4) for liver fibrosis model. The roles of AcSDKP on hepatic stellate cells (HSCs) were detected in vitro using isolated cells treated by TGF-ß1. The m6A profie of HSCs was screened by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results demonstrated that AcSDKP inhibited apoptosis through Hedgehog pathway in the CCl4-induced rat HSCs. Moreover, the administration of AcSDKP decreased the N6-methyladenosine (m6A) methyltransferase WTAP (Wilms' tumour 1-associated protein) expression. Mechanistically, WTAP targeted the 3'-UTR of Ptch1 mRNA, and administration of AcSDKP reduced the stability of Ptch1 mRNA. Thus, these findings revealed an anti-fibrosis axis of AcSDKP/WTAP/m6A/Ptch1 in liver fibrosis. Our results identify a novel role of AcSDKP in liver fibrosis via m6A modification and Hedgehog pathway, which helps us to shed light on the molecular mechanism in liver fibrosis progression.
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Proteínas Hedgehog/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligopéptidos/farmacología , Receptor Patched-1/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Genes del Tumor de Wilms , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Masculino , Glicoproteínas de Membrana/genética , Proteínas del Tejido Nervioso/genética , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.
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Neoplasias Renales , Insuficiencia Renal , Proteínas WT1 , Tumor de Wilms , Niño , Preescolar , Femenino , Genes del Tumor de Wilms , Humanos , Lactante , Riñón/patología , Riñón/cirugía , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Mutación , Recurrencia Local de Neoplasia/genética , Diálisis Renal , Insuficiencia Renal/genética , Estudios Retrospectivos , Proteínas WT1/genética , Tumor de Wilms/genética , Tumor de Wilms/patología , Tumor de Wilms/cirugíaRESUMEN
BackgroundThere is strong evidence of a genetic contribution to Wilms tumor, such as WT1 gene variation or epigenetic changes at chromosome locus 11p15. A previous genome wide association study (GWAS) of Wilms tumor identified other significant association loci including Xp22. Case report: A 4-year-old girl developed a Wilms tumor of the left isthmus of a horseshoe kidney. Chromosomal microarray analysis (CMA) of peripheral blood showed a 563 kb copy number gain at Xp22.11 that included PRDX4 and ZFX. PRDX4 has been shown to play an active role in the tumorigenesis of malignant neoplasms in various organs. Beckwith-Wiedemann methylation analysis and WT1 sequencing were negative. Whole exome sequencing of peripheral blood revealed pathogenic variant in PMS2 gene (c.765C > A), which is consistent with Lynch syndrome. Conclusion: We report a case of Wilms tumor with germline Xp22.11 duplication which further supports this locus as germline susceptibility alteration for Wilms Tumor.
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Riñón Fusionado , Neoplasias Renales , Tumor de Wilms , Preescolar , Femenino , Riñón Fusionado/genética , Genes del Tumor de Wilms , Estudio de Asociación del Genoma Completo , Células Germinativas/patología , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Tumor de Wilms/genética , Tumor de Wilms/patologíaRESUMEN
BACKGROUND: Nephrotic syndrome appears as a group of symptoms like proteinuria, edema and hyperlipidemia. Identification of monogenic forms revealed the physiology and pathogenesis of the SRNS. METHODS AND RESULTS: We performed Illumina panel sequencing of seven genes in 90 Indian patients to determine the role of these genetic mutations in nephrotic syndrome prognosis. Samtool was used for variants calling, and SnpEff and Snpsift did variants annotation. Clinical significance and variant classification were performed by the ClinVar database. In SSNS and SRNS patients, we found 0.78% pathogenic and 3.41% likely pathogenic mutations. Pathogenic mutations were found in LAMB2, LMX1B and WT1 genes, while likely pathogenic mutations were found in (6/13) LAMB2, (2/13) LMX1B, (2/13) TRPC6, (2/13) PTPRO and (1/13) PMM2 genes. Approximately 46% likely pathogenic mutations were contributed to the LAMB2 gene in SSNS and SRNS patients. We also detect 30 VUS (variants of uncertain significance), which were found (17/30) pathogenic and (13/30) likely pathogenic by different prediction tools. CONCLUSIONS: Multigene panels were used for genetic screening of heterogeneous disorders like nephrotic syndrome in the Indian population. We found pathogenic, likely pathogenic and certain VUS, which were responsible for the pathogenesis of the disease. Therefore, mutational analysis of SSNS and SRNS is necessary to avoid adverse effects of corticosteroids, modify the intensity of immunosuppressing agents, and prevent the disease's progression.
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Predisposición Genética a la Enfermedad , Mutación , Síndrome Nefrótico/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Genes del Tumor de Wilms , Humanos , Proteínas con Homeodominio LIM/genética , Laminina/genética , Masculino , Fosfotransferasas (Fosfomutasas)/genética , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Canal Catiónico TRPC6/genética , Factores de Transcripción/genéticaRESUMEN
Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.