Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.776
Filtrar
1.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(2): 184-192, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33624590

RESUMO

OBJECTIVE: To investigate the role of the differential piRNA NU13 derived from piwil2-induced cancer stem-like cells (piwil2-iCSCs) in regulating biological behaviors of Wilms tumor cells (G401). OBJECTIVE: The expressions of piRNA NU13 and NOP56 were detected in Wilms tumor cell line G401 using RT-qPCR. G401 cells were transfected with piRNA NU13 mimics and inhibitor for its over-expression and inhibition, and the transfection efficiency was verified with RT-qPCR. The changes in proliferation of G401 cells after transfection were detected using CCK8 assay, and cell apoptosis was analyzed using flow cytometry. Wound healing assay and Transwell assay were performed to examine the changes in migration and invasion abilities of the transfected cells. The binding of NOP56 and piRNA NU13 was detected using dual luciferase experiment. The protein expressions of MMP2, MMP9, BAX, Bcl2, and NOP56 in the cells were detected with Western blotting. OBJECTIVE: RTqPCR showed that the expression of piRNA NU13 decreased significantly in human Wilms tumor G401 cells as compared with that in renal tubular epithelial cell line HK2 (P < 0.05), and NOP56 was highly expressed in G401 cells and Wilms tumor tissues (P < 0.05). Over-expression of piRNA NU13 significantly suppressed the proliferation, migration and invasion of G401 cells, promoted cell apoptosis (P < 0.05), inhibited the expression of MMP2, MMP9 and Bcl2, and enhanced the expression of BAX (P < 0.05). The results of dual luciferase experiment showed that piRNA NU13 did not bind to NOP56 directly but regulated the expression of NOP56 in an indirect manner. OBJECTIVE: piRNA NU13 is down-regulated and NOP56 is highly expressed in Wilms tumor. piNU13 may regulate the expression of NOP56 indirectly to inhibit the proliferation, migration and invasion and promote apoptosis of Wilms tumor cells in vitro.


Assuntos
Neoplasias Renais , MicroRNAs , Tumor de Wilms , Proteínas Argonauta , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Renais/genética , Invasividade Neoplásica , RNA Interferente Pequeno/genética , Tumor de Wilms/genética
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(9): 1246-1252, 2020 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-32990223

RESUMO

OBJECTIVE: To predict and verify the target gene of miR-200c-3p and evaluate the inhibitory effect of miR-200c-3p on the proliferation of nephroblastoma cells. METHODS: The putative target genes of miR-200c-3p were predicted by bioinformatics approach. Nephroblastoma cell models with miR-200c-3p overexpression or knockdown were established in SK-NEP-1 and G401 cells with corresponding control groups. The expressions of CCNE2 in SK-NEP-1 and G401 cells in different groups were detected by RT-PCR and Western blotting. A luciferase reporter assay was used to determine the targeting relationship between miR-200c-3p and CCNE2. The effects of miR-200c-3p overexpression or knockdown on cell proliferation was detected by cell counting kit-8 (CCK-8) assay and soft agarose assay. RESULTS: CCNE2 was one of the target genes of miR-200c-3p as predicted by bioinformatics methods. Transfection of the two nephroblastoma cell lines with miR-200c-3p mimic resulted in significantly lowered CCNE2 mRNA and protein expressions (P < 0.05). The results of dual-luciferase assay confirmed that miR-200c-3p bound to the 3'UTR of CCNE2. CCK-8 assay and soft agarose assay demonstrated that overexpression of miR-200c-3p significantly inhibited the proliferation of the nephroblastoma cells (P < 0.01), and knocking down miR-200c-3p in the cells produced the opposite effects. CONCLUSIONS: miR-200c-3p overexpression inhibits the proliferation of nephroblastoma cells by down-regulating its target gene CCNE2.


Assuntos
Neoplasias Renais , MicroRNAs/genética , Tumor de Wilms , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclinas , Humanos , Neoplasias Renais/genética , Invasividade Neoplásica , Tumor de Wilms/genética
4.
Gene ; 754: 144839, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504654

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Fatores de Processamento de RNA/genética , Tumor de Wilms/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/patologia , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Prognóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/patologia
5.
Crit Rev Oncol Hematol ; 150: 102970, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32371339

RESUMO

To characterize metanephric tumours in children, we performed a literature review investigating paediatric metanephric adenomas (MA), metanephric stromal tumours (MST) and metanephric adenofibromas (MAF). Including two patients from our own institution (MA, MAF), 110 individual cases (41 MA, 20 MAF, 49 MST) were identified. Additionally, fifteen composite tumours were identified, with areas of MA/MAF and Wilms tumour (WT) or papillary carcinoma. No distinct clinical or radiological features could be defined. In pure metanephric tumours, histologically proven distant metastases were reported once (MA), relapse was reported once (MST) and one tumour-related death occurred (MST). Somatic BRAF-V600E mutations were tested in 15 cases, and identified in 3/6 MA, 3/3 MAF, and 6/6 MST. In our institution the MA harboured a somatic KRAS-G12R mutation. Overall, paediatric metanephric tumours are difficult to discriminate from other renal tumours at presentation, behave relatively benign, and the occurrence of composite tumours warrants analysis of underlying (genetic) pathways.


Assuntos
Adenoma/genética , Adenoma/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Tumor de Wilms/genética , Tumor de Wilms/patologia , Biomarcadores Tumorais/genética , Criança , Análise Mutacional de DNA , Humanos , Imuno-Histoquímica , Imunofenotipagem , Recidiva Local de Neoplasia
6.
Nat Commun ; 11(1): 2619, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457326

RESUMO

DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3'-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation.


Assuntos
Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Exorribonucleases/metabolismo , Macrossomia Fetal/microbiologia , RNA Mensageiro/metabolismo , Tumor de Wilms/microbiologia , Animais , Sinalização do Cálcio/genética , Diferenciação Celular , Células-Tronco Embrionárias , Exorribonucleases/deficiência , Exorribonucleases/genética , Macrossomia Fetal/enzimologia , Macrossomia Fetal/genética , Regulação da Expressão Gênica , Humanos , Insulina/metabolismo , Camundongos , Biossíntese de Proteínas , RNA Citoplasmático Pequeno/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo , Uridina Monofosfato/metabolismo , Tumor de Wilms/enzimologia , Tumor de Wilms/genética
7.
Nat Commun ; 11(1): 1310, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161258

RESUMO

Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine.


Assuntos
Bancos de Espécimes Biológicos , Neoplasias Renais/genética , Rim/patologia , Organoides/patologia , Adolescente , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Técnicas de Cultura de Células/métodos , Criança , Pré-Escolar , Metilação de DNA , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Técnicas de Genotipagem , Humanos , Lactente , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Nefroma Mesoblástico/tratamento farmacológico , Nefroma Mesoblástico/genética , Nefroma Mesoblástico/patologia , Países Baixos , Medicina de Precisão/métodos , RNA-Seq , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única , Transfecção , Células Tumorais Cultivadas , Sequenciamento Completo do Genoma , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/genética , Tumor de Wilms/patologia , Adulto Jovem
9.
Eur Rev Med Pharmacol Sci ; 24(1): 97-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31957822

RESUMO

OBJECTIVE: Wilms' tumor (WT) is the most common malignant renal tumor in children. MicroRNAs (MiRNAs) function in the progression of various cancers. Recent reports have reported that miR-140-5p and miR-92a-3p are dysregulated in WT tissues, but the potential mechanisms of the two miRNAs in modulating WT progression are still poorly understood. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was conducted to detect the expression levels of miR-140-5p, miR-92a-3p, and fibroblast growth factor receptor substrate 2 (FRS2) in WT tissues and cells, as well as matched controls. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry assay were employed to check cell proliferation and apoptosis, respectively. The abilities of cell migration and invasion were evaluated by transwell assay. The protein level of FRS2 in samples was measured by Western blot. The starBase was used to predict the binding sites between FRS2 and miR-140-5p or miR-92a-3p and the Dual-Luciferase reporter assay was performed to verify the interaction. Xenograft tumor model was established to investigate the biological roles of the two miRNAs in WT in vivo. RESULTS: The levels of miR-140-5p and miR-92a-3p were significantly downregulated in WT tissues and cells, while the expression of FRS2 was significantly upregulated. The two miRNAs both inhibited proliferation, migration, invasion, and induced apoptosis of WT cells. Besides, FRS2 was a target of the two miRNAs and its overexpression reversed the effects of the two miRNAs-mediated suppression on WT progression. Moreover, the upregulation of the two miRNAs repressed tumor growth in vivo. CONCLUSIONS: MiR-140-5p and miR-92a-3p attenuated the aggressive progression of WT via targeting FRS2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Neoplasias Renais/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Tumor de Wilms/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tumor de Wilms/genética , Tumor de Wilms/patologia
10.
Eur J Pediatr ; 179(2): 191-202, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897843

RESUMO

Cell-free DNA profiling using patient blood is emerging as a non-invasive complementary technique for cancer genomic characterization. Since these liquid biopsies will soon be integrated into clinical trial protocols for pediatric cancer treatment, clinicians should be informed about potential applications and advantages but also weaknesses and potential pitfalls. Small retrospective studies comparing genetic alterations detected in liquid biopsies with tumor biopsies for pediatric solid tumor types are encouraging. Molecular detection of tumor markers in cell-free DNA could be used for earlier therapy response monitoring and residual disease detection as well as enabling detection of pathognomonic and therapeutically relevant genomic alterations.Conclusion: Existing analyses of liquid biopsies from children with solid tumors increasingly suggest a potential relevance for molecular diagnostics, prognostic assessment, and therapeutic decision-making. Gaps remain in the types of tumors studied and value of detection methods applied. Here we review the current stand of liquid biopsy studies for pediatric solid tumors with a dedicated focus on cell-free DNA analysis. There is legitimate hope that integrating fully validated liquid biopsy-based innovations into the standard of care will advance patient monitoring and personalized treatment of children battling solid cancers.What is Known:• Liquid biopsies are finding their way into routine oncological screening, diagnosis, and disease monitoring in adult cancer types fast.• The most widely adopted source for liquid biopsies is blood although other easily accessible body fluids, such as saliva, pleural effusions, urine, or cerebrospinal fluid (CSF) can also serve as sources for liquid biopsiesWhat is New:• Retrospective proof-of-concept studies in small cohorts illustrate that liquid biopsies in pediatric solid tumors yield tremendous potential to be used in diagnostics, for therapy response monitoring and in residual disease detection.• Liquid biopsy diagnostics could tackle some long-standing issues in the pediatric oncology field; they can enable accurate genetic diagnostics in previously unbiopsied tumor types like renal tumors or brain stem tumors leading to better treatment strategies.


Assuntos
Biópsia Líquida/métodos , Oncologia/métodos , Neoplasias/patologia , Neoplasias/terapia , Neuroblastoma/patologia , Tumor de Wilms/patologia , Criança , Feminino , Previsões , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias/genética , Neoplasias/mortalidade , Neuroblastoma/genética , Neuroblastoma/mortalidade , Pediatria/métodos , Análise de Sobrevida , Tumor de Wilms/genética , Tumor de Wilms/mortalidade
11.
J Pediatr Hematol Oncol ; 42(3): e128-e131, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31574018

RESUMO

BACKGROUND AND AIM: Wilms tumor (WT) is the most common childhood malignant renal tumor. Germline mutations in several WT predisposition genes have been identified. However, the fundamental cause of most WT patients remains unexplained. Recently, a founder mutation, c.1060C>T (p. Arg254X) in a mitotic spindle checkpoint gene, TRIP13, was reported in 5 unrelated children with WT from the United Kingdom, of Pakistani descent from Azad Kashmir region. This observation suggests other children with WT in Pakistan may also harbor this mutation. We conducted the first study to assess the contribution of TRIP13 c.1060C>T mutation to WT in Pakistan. MATERIALS AND METHODS: Constitutional genomic DNA from 68 Pakistani individuals including unrelated WT cases (n=26) and one (n=10) or both (n=32) of their parent(s) were screened for the TRIP13 c.1060C>T mutation using DNA sequence analysis. We also included positive controls in the analyses. RESULTS: The median age of WT diagnosis was 3.0 years (range, 0.75 to 10). The TRIP13 c.1060C>T mutation was not found in any WT patient (n=26) or their parents (n=42). Twenty-four patients (92.4%) presented with unilateral tumor and 2 patients (7.7%) were diagnosed with synchronous bilateral WT. Thirteen patients (50%) reported parental consanguinity. Thirteen patients (50.0%) belonged to the Punjabi ethnicity and 1 patient (3.8%) had a Kashmiri background. Four patients (16.7%) reported a family history of WT or other malignancies. The predominant histologic subtype was stromal (46.2%). The majority of patients presented with >5 cm of tumor size (81%). None of the patients had a personal or family history of congenital anomalies, or associated genetic syndromes. CONCLUSIONS: Our findings suggest that TRIP13 c.1060C>T mutation may be infrequent in Pakistani WT cases. Further evaluation of this mutation in a large number of WT patients of Kashmiri heritage and various ethnic backgrounds from Pakistan is warranted.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Proteínas de Ciclo Celular/genética , Genes do Tumor de Wilms , Neoplasias Renais/genética , Tumor de Wilms/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Mutação , Paquistão
12.
Int J Cancer ; 146(4): 1010-1017, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31286500

RESUMO

Over 10% of children with Wilms tumor (WT) have an underlying cancer predisposition syndrome (CPS). Cognizant of increasing demand for genetic evaluation and limited resources across health care settings, there is an urgent need to rationalize genetic referrals for this population. The McGill Interactive Pediatric OncoGenetic Guidelines study, a Canadian multi-institutional initiative, aims to develop an eHealth tool to assist physicians in identifying children at elevated risk of having a CPS. As part of this project, a decisional algorithm specific to WT consisting of five tumor-specific criteria (age <2 years, bilaterality/multifocality, stromal-predominant histology, nephrogenic rests, and overgrowth features) and universal criteria including features of family history suspicious for CPS and congenital anomalies, was developed. Application of the algorithm generates a binary recommendation-for or against genetic referral for CPS evaluation. To evaluate the algorithm's sensitivity for CPS identification, we retrospectively applied the tool in consecutive pediatric patients (n = 180) with WT, diagnosed and/or treated at The Hospital for Sick Children (1997-2016). Odds ratios were calculated to evaluate the strengths of associations between each criterion and specific CPS subtypes. Application of the algorithm identified 100% of children with WT and a confirmed CPS (n = 27). Age <2 years, bilaterality/multifocality, and congenital anomalies were strongly associated with pathogenic variants in WT1. Presence of >1 overgrowth feature was strongly associated with Beckwith-Wiedemann syndrome. Stromal-predominant histology did not contribute to CPS identification. We recommend the incorporation of the WT algorithm in the routine assessment of children with WT to facilitate prioritization of genetic referrals in a sustainable manner.


Assuntos
Sistemas de Apoio a Decisões Clínicas/normas , Testes Genéticos/normas , Neoplasias Renais/diagnóstico , Encaminhamento e Consulta/normas , Telemedicina/métodos , Tumor de Wilms/diagnóstico , Adolescente , Algoritmos , Canadá , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Proteínas WT1/genética , Tumor de Wilms/genética , Tumor de Wilms/patologia
13.
Cancer Metastasis Rev ; 38(4): 643-655, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31811552

RESUMO

Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.


Assuntos
Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/genética , Adolescente , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Criança , Humanos , Neoplasias Renais/patologia , Camundongos , Terapia de Alvo Molecular , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Tumor de Wilms/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Science ; 366(6470): 1247-1251, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806814

RESUMO

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.


Assuntos
Células Clonais , Metilação de DNA , Neoplasias Renais/genética , Rim/patologia , Lesões Pré-Cancerosas/patologia , Tumor de Wilms/genética , Criança , Humanos , Rim/embriologia , Neoplasias Renais/patologia , Mutação , Filogenia , Tumor de Wilms/patologia
15.
Genes (Basel) ; 10(12)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861090

RESUMO

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed.


Assuntos
Aniridia/genética , Proteínas do Olho/genética , Estudos de Associação Genética , Fator de Transcrição PAX6/genética , Aniridia/patologia , Bases de Dados Genéticas , Deleção de Genes , Haploinsuficiência , Humanos , Mutação de Sentido Incorreto , Tumor de Wilms/genética , Tumor de Wilms/patologia
16.
Nat Commun ; 10(1): 5806, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862972

RESUMO

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Evolução Clonal , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Renais/genética , Tumor de Wilms/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos SCID , Sequenciamento Completo do Exoma , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
BMC Med Genomics ; 12(1): 194, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842887

RESUMO

BACKGROUND: Competitive endogenous RNAs (ceRNAs) have revealed a new mechanism of interaction between RNAs. However, an understanding of the ceRNA regulatory network in Wilms tumour (WT) remains limited. METHODS: The expression profiles of mRNAs, miRNAs and lncRNAs in Wilms tumour samples and normal samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. The EdgeR package was employed to identify differentially expressed lncRNAs, miRNAs and mRNAs. Functional enrichment analyses via the ClusterProfile R package were performed, and the lncRNA-miRNA-mRNA interaction ceRNA network was established in Cytoscape. Subsequently, the correlation between the ceRNA network and overall survival was analysed. RESULTS: A total of 2037 lncRNAs, 154 miRNAs and 3609 mRNAs were identified as differentially expressed RNAs in Wilms tumour. Of those, 205 lncRNAs, 26 miRNAs and 143 mRNAs were included in the ceRNA regulatory network. The results of Gene Ontology (GO) analysis revealed that the differentially expressed genes (DEGs) were mainly enriched in terms related to response to mechanical stimuli, transcription factor complexes, and transcription factor activity (related to RNA polymerase II proximal promoter sequence-specific DNA binding). The results of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the DEGs were mainly enriched in pathways related to the cell cycle. The survival analysis results showed that 16 out of the 205 lncRNAs, 1 out of 26 miRNAs and 5 out of 143 mRNAs were associated with overall survival in Wilms tumour patients (P < 0.05). CONCLUSIONS: CeRNA networks play an important role in Wilms tumour. This finding might provide effective, novel insights for further understanding the mechanisms underlying Wilms tumour.


Assuntos
Redes Reguladoras de Genes , Neoplasias Renais/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Tumor de Wilms/genética , Carcinogênese/genética , Progressão da Doença , Humanos , Neoplasias Renais/patologia , RNA Mensageiro/genética , Tumor de Wilms/patologia
18.
Cell Rep ; 29(6): 1675-1689.e9, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31693904

RESUMO

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neurofibromina 1/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Genômica , Humanos , Camundongos , Mutação , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Recidiva , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Exoma , Tumor de Wilms/genética , Tumor de Wilms/metabolismo
19.
Arkh Patol ; 81(5): 80-88, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626209

RESUMO

The paper describes 2 cases of immature ovarian teratoma with elements of nephroblastoma (ICD-0 code 9080/3) in patients aged 61 and 70 years. Microscopic examination revealed that both cases had blastemal cells with scant cytoplasm and basophil nuclei sticking together. Epidermal, glandular, rhabdomyoblastic, chondroid, bone, neuroectodermal, and histiocytic components were determined. Papillary and glomeruloid structures and primitive tubules were immured in the sarcomatous stroma. Immunohistochemical studies showed a strong reaction with Wilms tumor 1 (WT1), paired box gene (PAX-2), cytokeratin 7, desmin, smooth muscle actin, and α-1 antitrypsin. The recurrent tumors displayed a 1.8- to 6.1-fold increase in the level of p53. At the same time, the molecular genetic study revealed p53 gene mutation. In both cases, serous ovarian cystadenocarcinoma was misdiagnosed, ineffective chemotherapy was performed, and a recurrence occurred. The literature review revealed only 8 such cases.


Assuntos
Neoplasias Renais/patologia , Neoplasias Ovarianas/patologia , Teratoma/patologia , Tumor de Wilms/patologia , Idoso , Feminino , Humanos , Neoplasias Renais/genética , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Teratoma/genética , Tumor de Wilms/genética
20.
J Gene Med ; 21(12): e3133, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31657076

RESUMO

BACKGROUND: Wilms tumor, a frequently occurring pediatric renal cancer worldwide, originated from the embryonal nephric mesenchyme. However, epidemiological data on the association between LINC00673 polymorphisms and Wilms tumor risk are scant. This case-control study was conducted to investigate the potential role of the LINC00673 rs11655237 C>T polymorphism in the susceptibility to Wilms tumor. METHODS: In the present study, we conducted a genotyping analysis of LINC00673 rs11655237 C>T in 414 cases and 1199 controls recruited from five hospitals in China. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models to determine the association of LINC00673 rs11655237 C>T polymorphism and Wilms tumor susceptibility. RESULTS: No significant association between the LINC00673 rs11655237 C>T polymorphism and Wilms tumor risk was observed (CT versus CC: adjusted OR = 0.90, 95% CI = 0.71-1.15; TT versus CC: adjusted OR = 0.86, 95% CI = 0.50-1.49; TT/CT versus CC: adjusted OR = 0.90, 95% CI = 0.71-1.13; and TT versus CC/CT: adjusted OR = 0.89, 95% CI = 0.52-1.53). We also failed to make any remarkable findings for this genotype in the stratification analysis. CONCLUSIONS: In summary, we failed to provide any evidence in favor of the significant susceptibility of rs11655237 C>T polymorphism in LINC00673 to Wilms tumor. These data could be useful for reinforcing our understanding of the potential contribution of LINC00673 rs11655237 C>T to Wilms tumor susceptibility.


Assuntos
Alelos , Predisposição Genética para Doença , Genótipo , RNA Longo não Codificante/genética , Tumor de Wilms/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Estadiamento de Neoplasias , Razão de Chances , Tumor de Wilms/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...