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1.
Pediatr Blood Cancer ; 66(3): e27549, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30408319

RESUMO

BACKGROUND: Two principal approaches to Wilms tumor (WT) treatment are immediate surgery (IS) and preoperative chemotherapy (PCT), and both treatments use the risk-adapted approach that includes histological subclassification of the tumor, combined with additional prognostic factors. In the UKW3 trial, these two approaches were compared. The aim of the present study was to compare histological features between the two groups, to assess the impact of PCT on distribution of histological subtyping and staging and to evaluate whether PCT resulted in more staging discrepancies between local and central pathology review (CPR). MATERIALS AND METHODS: The cases were identified from the UKW3 trial database. The criteria for inclusion in the study were unilateral, nonmetastatic, nonanaplastic WTs, and submitted for CPR with an adequate number of slides. They were subclassified according to the NWTS and later the SIOP 9301 criteria. RESULTS: There were 244 WTs in the IS and 182 in the PCT group subclassified as follows: blastemal 86 (35%) vs 9 (5%), epithelial 34 (14%) vs 12 (7%), stromal 12 (5%) vs 25 (14%), mixed 112 (46%) vs 45 (25%), respectively, plus 40% regressive and 10% completely necrotic WTs in the PCT group. The differences between the two groups for blastemal and mixed types were statistically significant. In the PCT group, there was a significant decrease in stage III tumors. The discrepancies in staging between local and CPR were not significant. CONCLUSION: PCT significantly altered histological features and typing of WTs. It resulted in fewer stage III tumors, and staging discrepancies were equally represented in both groups.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/patologia , Cuidados Pré-Operatórios , Tumor de Wilms/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Renais/tratamento farmacológico , Masculino , Prognóstico , Taxa de Sobrevida , Reino Unido , Tumor de Wilms/tratamento farmacológico
2.
J Pathol ; 244(2): 242-253, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29160922

RESUMO

Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20- to 40-year age group. Although most cases show sensitivity to cis-platinum-based chemotherapy, this is associated with long-term toxicities and chemo-resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor-1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long-term shRNA-mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small-molecule IGF1R inhibitor NVP-AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin-resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Testiculares/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia
3.
EBioMedicine ; 9: 120-129, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27333041

RESUMO

The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.


Assuntos
Neoplasias Renais/patologia , Perda de Heterozigosidade/fisiologia , Tumor de Wilms/patologia , Alelos , Biomarcadores Tumorais/genética , Pré-Escolar , Cromossomos Humanos Par 11 , Evolução Clonal , Feminino , Dosagem de Genes , Genoma , Humanos , Lactente , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Imageamento por Ressonância Magnética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Tumor de Wilms/diagnóstico por imagem , Tumor de Wilms/genética
4.
PLoS One ; 9(10): e109924, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25313908

RESUMO

PURPOSE: The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. PATIENTS AND METHODS: We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. RESULTS: From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. CONCLUSION: This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Renais/genética , Rim/patologia , Recidiva Local de Neoplasia/genética , Proteína Supressora de Tumor p53/genética , Tumor de Wilms/genética , Anaplasia/genética , Anaplasia/metabolismo , Anaplasia/mortalidade , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Mutação da Fase de Leitura , Estudos de Associação Genética , Instabilidade Genômica , Humanos , Lactente , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Transcriptoma , Tumor de Wilms/metabolismo , Tumor de Wilms/mortalidade
5.
Pediatr Dev Pathol ; 16(3): 217-23, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23387809

RESUMO

Wilms tumor (WT) with diffuse anaplasia has an unfavorable prognosis and is often (>70%) associated with mutations in the TP53 gene. Although most WTs are unilateral, 5-10% are bilateral, and they are almost always present with nephrogenic rests. The latter are considered a precursor of WT. Two cases of bilateral WTs with nephroblastomatosis, in which anaplastic changes were detected over a period of time, were analyzed using clinical, radiological, histopathological, and molecular-genetic data. TP53 was analyzed by direct sequencing of its full coding sequence and intron-exon boundaries in 11 fragments. DNA was extracted from paraffin-embedded or frozen specimens. High-resolution genomic copy number profiling was carried out by UCL Genomics on the Affymetrix Human Mapping 250K Nsp or Genome-Wide Human SNP Array 6.0 platform. Both cases demonstrated a strong association between the appearance of anaplastic clones and TP53 mutations. Synchronous ganglioneuroma was diagnosed in one case. Our cases are unique as they represent a long disease history and demonstrate the difficulties in managing rare cases of bilateral WT with anaplasia. These cases also emphasize the practical importance of modern molecular-genetic techniques and their clinical application. Moreover, they highlight the issue of the adequate sampling needed in order to gather comprehensive, efficient, and sufficient information about genetic events in a single tumor.


Assuntos
Genes p53/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Tumor de Wilms/genética , Tumor de Wilms/patologia , Anaplasia , Pré-Escolar , Feminino , Dosagem de Genes , Humanos , Masculino , Mutação , Reação em Cadeia da Polimerase
6.
Pediatr Dev Pathol ; 14(3): 189-93, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21054158

RESUMO

Wilms tumor is the most common renal tumor of childhood. However, other epithelial, mesenchymal, and neuroectodermal neoplasms may also arise in the kidney during childhood, several of which show specific age distributions; in the 1st year of life, mesoblastic nephroma and rhabdoid tumor are more common, whereas renal cell carcinoma, primitive neuroectodermal tumor, and anaplastic Wilms tumors are relatively more frequent in older children and adolescents. The aim of this study is to describe the spectrum of renal tumors in children aged 10-16 years using data from 1492 patients registered in the UK Wilms Tumour 3 Trial (1991-2001) and International Society of Paediatric Oncology Wilms Tumour Trial 2001 (2002-2008) clinical trials of renal tumors in childhood. There were 67 (4.6%) tumors in children aged 10-16 years: 50 Wilms tumors (74.6%), 10 (14.9%) renal cell carcinomas, 3 (4.5%) renal medullary carcinomas, 2 (3%) primitive neuroectodermal tumors, 1 clear cell sarcoma of kidney, and 1 desmoplastic small round cell tumor. Fourteen percent of the Wilms tumors in this age group had diffuse anaplasia. Among the 10 renal cell carcinomas, 4 were associated with t(Xp-11.2), 3 were of papillary type II, 1 was papillary type I, 1 was clear cell type, and 1 was unclassified. Five-year overall survival for Wilms tumor was 63% (43% for anaplastic tumors), significantly lower than reported overall survival for all pediatric Wilms tumors. Only 40% of patients with renal cell carcinoma survived, and all patients with other tumors died.


Assuntos
Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Adolescente , Distribuição por Idade , Criança , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Reino Unido
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