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1.
Nat Genet ; 39(2): 165-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17200668

RESUMO

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.


Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteína BRCA2/fisiologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
2.
Nat Genet ; 38(11): 1239-41, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17033622

RESUMO

We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Penetrância , RNA Helicases/genética , Adulto , Códon sem Sentido , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Linhagem
3.
Nat Genet ; 38(8): 873-5, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16832357

RESUMO

We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.


Assuntos
Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Alelos , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Linhagem
4.
Genes Chromosomes Cancer ; 50(12): 982-95, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21882282

RESUMO

Anaplasia in Wilms tumor, a distinctive histology characterized by abnormal mitoses, is associated with poor patient outcome. While anaplastic tumors frequently harbour TP53 mutations, little is otherwise known about their molecular biology. We have used array comparative genomic hybridization (aCGH) and cDNA microarray expression profiling to compare anaplastic and favorable histology Wilms tumors to determine their common and differentiating features. In addition to changes on 17p, consistent with TP53 deletion, recurrent anaplasia-specific genomic loss and under-expression were noted in several other regions, most strikingly 4q and 14q. Further aberrations, including gain of 1q and loss of 16q were common to both histologies. Focal gain of MYCN, initially detected by high resolution aCGH profiling in 6/61 anaplastic samples, was confirmed in a significant proportion of both tumor types by a genomic quantitative PCR survey of over 400 tumors. Overall, these results are consistent with a model where anaplasia, rather than forming an entirely distinct molecular entity, arises from the general continuum of Wilms tumor by the acquisition of additional genomic changes at multiple loci.


Assuntos
Anaplasia/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 4 , Neoplasias Renais/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Tumor de Wilms/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Análise em Microsséries/métodos , Proteína Proto-Oncogênica N-Myc , Recidiva Local de Neoplasia/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sobrevida
5.
Hum Pathol ; 86: 182-192, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30594749

RESUMO

The tumor suppressor TP53 promotes nerve growth factor receptor (NTRK1) -Y674/Y675 phosphorylation (NTRK1-pY674/pY675) via repression of the NTRK1 phosphatase PTPN6 in a ligand-independent manner, resulting in suppression of breast cancer cell proliferation. Moreover, NTRK1-pY674/pY675 together with low levels of PTPN6 and TP53 expression is associated with favorable disease-free survival of breast cancer patients. We determined whether in neuroblastoma this protein expression pattern impacts relapse-free survival (RFS). NTRK1-pY674/pY675, PTPN6, and TP53 expression was assessed in 98 neuroblastoma samples by immunohistochemistry. Association between expression levels and RFS was investigated by multivariate and Kaplan-Meier analysis. Mutant or wild-type TP53 was identified by sequencing tumor DNA. Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology. Similar results were observed with tumors expressing wild-type TP53, NTRK1-pY674/pY675 and low or undetectable levels of PTPN6. Kaplan-Meier analysis demonstrated a significant correlation (P = .004), with a 50% probability of RFS (median survival 4.73 years) when present compared with 19.51% (median survival 11.63 months) when absent. Similar results were seen with non-amplified MYCN or unfavorable/undifferentiating samples and tumors from patients aged 18 months or less. Importantly, NTRK1-pY674/pY675 is an independent predictor of improved RFS. These results strongly suggest that NTRK1-pY674/pY675 together with wild-type TP53 and undetectable or low levels of PTPN6 expression is a potential biomarker of improved RFS of neuroblastoma patients. The predictive value of NTRK1-pY674/pY675 together with wild-type TP53 and low PTPN6 expression could contribute to neuroblastoma patient prognosis.


Assuntos
Neuroblastoma/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptor trkA/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Biomarcadores Tumorais , Criança , Pré-Escolar , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Fosforilação , Prognóstico , Taxa de Sobrevida
6.
Transl Oncol ; 11(6): 1301-1306, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30172241

RESUMO

BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 µl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/µl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.

7.
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
8.
J Clin Oncol ; 34(26): 3195-203, 2016 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-27432915

RESUMO

PURPOSE: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. MATERIALS AND METHODS: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. RESULTS: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. CONCLUSION: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Variações do Número de Cópias de DNA , Terapia Neoadjuvante , Nefrectomia , Tumor de Wilms/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Nefrectomia/efeitos adversos , Nefrectomia/mortalidade , Fenótipo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Tumor de Wilms/genética , Tumor de Wilms/mortalidade , Tumor de Wilms/patologia
9.
Genome Med ; 7(1): 11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25763109

RESUMO

BACKGROUND: Wilms tumours (WTs) are characterised by several hallmarks that suggest epimutations such as aberrant DNA methylation are involved in tumour progression: loss of imprinting at 11p15, lack of recurrent mutations and formation of nephrogenic rests (NRs), which are lesions of retained undifferentiated embryonic tissue that can give rise to WTs. METHODS: To identify such epimutations, we performed a comprehensive methylome analysis on 20 matched trios of micro-dissected WTs, NRs and surrounding normal kidneys (NKs) using Illumina Infinium HumanMethylation450 Bead Chips and functionally validated findings using RNA sequencing. RESULTS: Comparison of NRs with NK revealed prominent tissue biomarkers: 629 differentially methylated regions, of which 55% were hypermethylated and enriched for domains that are bivalent in embryonic stem cells and for genes expressed during development (P = 2.49 × 10(-5)). Comparison of WTs with NRs revealed two WT subgroups; group-2 WTs and NRs were epigenetically indistinguishable whereas group-1 WTs showed an increase in methylation variability, hypomethylation of renal development genes, hypermethylation and relative loss of expression of cell adhesion genes and known and potential new WT tumour suppressor genes (CASP8, H19, MIR195, RB1 and TSPAN32) and was strongly associated with bilateral disease (P = 0.032). Comparison of WTs and NRs to embryonic kidney highlighted the significance of polycomb target methylation in Wilms tumourigenesis. CONCLUSIONS: Methylation levels vary during cancer evolution. We have described biomarkers related to WT evolution from its precursor NRs which may be useful to differentiate between these tissues for patients with bilateral disease.

10.
Oncotarget ; 6(9): 7232-43, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25749049

RESUMO

Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes myc , Neoplasias Renais/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor de Wilms/metabolismo , Metilação de DNA , Análise Mutacional de DNA , Intervalo Livre de Doença , Exoma , Dosagem de Genes , Perfilação da Expressão Gênica , Genes p53 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Mutação , Recidiva Local de Neoplasia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Prognóstico , Proto-Oncogene Mas , Proteína Supressora de Tumor p53/metabolismo , Tumor de Wilms/genética
11.
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
12.
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
13.
Clin Cancer Res ; 16(7): 2036-45, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20332316

RESUMO

PURPOSE: Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP). EXPERIMENTAL DESIGN: We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation-dependent Probe Amplification, or fluorescence in situ hybridization. RESULTS: We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in approximately 4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%). CONCLUSIONS: Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Dosagem de Genes , Neoplasias Renais/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Ubiquitina-Proteína Ligases/genética , Tumor de Wilms/genética , Criança , Cromossomos Humanos Par 2 , Proteína 7 com Repetições F-Box-WD , Feminino , Amplificação de Genes , Deleção de Genes , Dosagem de Genes/fisiologia , Genes do Tumor de Wilms , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/patologia , Mães , Mutação , Proteína Proto-Oncogênica N-Myc , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Tumor de Wilms/classificação , Tumor de Wilms/patologia
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