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1.
Blood ; 129(23): 3051-3058, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28411282

RESUMO

Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled in Children's Oncology Group (COG) studies AAML0531, AAML03P1, and CCG2961. Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy-number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction 1 (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.2-2.4; HR, 1.4; 95% CI, 1.0-1.8; and HR, 1.4; 95% CI, 1.0-2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard-risk group only (HR, 1.9; 95% CI, 1.1-3.3 and HR, 1.7; 95% CI, 1.1-2.6, respectively). Additional studies are required to test the prognostic significance of CNA presence in disease relapse in patients with AML. COG studies AAML0531, AAML03P1, and CCG2961 were registered at www.clinicaltrials.gov as #NCT01407757, #NCT00070174, and #NCT00003790, respectively.


Assuntos
Variações do Número de Cópias de DNA , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Criança , Pré-Escolar , Estudos de Coortes , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Marcadores Genéticos , Genótipo , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do Tratamento
2.
Nature ; 469(7329): 216-20, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21124317

RESUMO

Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Neuroblastoma/genética , Oncogenes/genética , Fatores de Transcrição/genética , Alelos , Linhagem Celular Tumoral , Proliferação de Células , Cromossomos Humanos Par 11/genética , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Europa (Continente)/etnologia , Duplicação Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Genômica , Genótipo , Humanos , Proteínas com Domínio LIM , Neuroblastoma/patologia , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Taxa de Sobrevida
3.
Pediatr Blood Cancer ; 63(2): 276-86, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26398108

RESUMO

BACKGROUND: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in preclinical models and clinical activity against several solid and hematological cancers. PROCEDURES: Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 µM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks. RESULTS: Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 µM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models. CONCLUSIONS: Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína Exportina 1
4.
Nature ; 459(7249): 987-91, 2009 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-19536264

RESUMO

Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.


Assuntos
Cromossomos Humanos Par 1/genética , Dosagem de Genes/genética , Variação Genética/genética , Neuroblastoma/genética , Criança , Quebra Cromossômica , Feto/metabolismo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , Reprodutibilidade dos Testes , População Branca/genética
5.
Nature ; 455(7215): 930-5, 2008 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-18724359

RESUMO

Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.


Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Neuroblastoma/enzimologia , Neuroblastoma/genética , Proteínas Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Sequência de Bases , Linhagem Celular Tumoral , Criança , Cromossomos Humanos Par 2/genética , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fosforilação , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases
6.
PLoS Genet ; 7(3): e1002026, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21436895

RESUMO

Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07 × 10⁻6), DDX4 and IL31RA both at 5q11.2 (P = 2.94 × 10⁻6 and 6.54 × 10⁻7 respectively), and HSD17B12 at 11p11.2 (P = 4.20 × 10⁻7) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma.


Assuntos
Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Neuroblastoma/genética , Fenótipo , Algoritmos , Pré-Escolar , Haplótipos , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologia , Polimorfismo de Nucleotídeo Único
7.
Proc Natl Acad Sci U S A ; 108(8): 3336-41, 2011 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-21289283

RESUMO

Neuroblastoma is a childhood cancer that is often fatal despite intense multimodality therapy. In an effort to identify therapeutic targets for this disease, we performed a comprehensive loss-of-function screen of the protein kinome. Thirty kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. CHK1 mRNA expression was higher in MYC-Neuroblastoma-related (MYCN)-amplified (P < 0.0001) and high-risk (P = 0.03) tumors. Western blotting revealed that CHK1 was constitutively phosphorylated at the ataxia telangiectasia response kinase target site Ser345 and the autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern was also seen in six of eight high-risk primary tumors but not in control nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and TCS2312, with median IC(50) values of 564 nM and 548 nM, respectively. In contrast, the control lines had high micromolar IC(50) values, indicating a strong correlation between CHK1 phosphorylation and CHK1 inhibitor sensitivity (P = 0.0004). Furthermore, cell cycle analysis revealed that CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, consistent with its role in replication fork progression. CHK1 inhibitor sensitivity correlated with total MYC(N) protein levels, and inducing MYCN in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, which caused growth inhibition when inhibited. These data show the power of a functional RNAi screen to identify tractable therapeutical targets in neuroblastoma and support CHK1 inhibition strategies in this disease.


Assuntos
Neuroblastoma/tratamento farmacológico , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/farmacologia , Apoptose/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/patologia , Proteínas Nucleares/análise , Proteínas Oncogênicas/análise , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro , Fase S/efeitos dos fármacos
8.
Genes Chromosomes Cancer ; 51(2): 174-85, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22045684

RESUMO

Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Regulação para Baixo , Glutationa S-Transferase pi/genética , Neoplasias do Sistema Nervoso/genética , Neuroblastoma/genética , Adolescente , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Criança , Pré-Escolar , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Glutationa S-Transferase pi/metabolismo , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Neoplasias do Sistema Nervoso/metabolismo , Neoplasias do Sistema Nervoso/mortalidade , Neoplasias do Sistema Nervoso/patologia , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Prognóstico , Regiões Promotoras Genéticas
9.
N Engl J Med ; 358(24): 2585-93, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18463370

RESUMO

BACKGROUND: Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known. METHODS: We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations. RESULTS: We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01). CONCLUSIONS: A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.


Assuntos
Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 6/genética , Neuroblastoma/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Pré-Escolar , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc , Estadiamento de Neoplasias , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética
10.
J Clin Oncol ; 38(31): 3685-3697, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32903140

RESUMO

PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038). CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Fatores Etários , Ensaios Clínicos como Assunto , Diploide , Amplificação de Genes , Genômica , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Prognóstico , Intervalo Livre de Progressão , Taxa de Sobrevida
11.
Mol Cancer Res ; 6(5): 735-42, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18505919

RESUMO

MicroRNAs are small noncoding RNAs that have critical roles in regulating a number of cellular functions through transcriptional silencing. They have been implicated as oncogenes and tumor suppressor genes (oncomirs) in several human neoplasms. We used an integrated genomics and functional screening strategy to identify potential oncomirs in the pediatric neoplasm neuroblastoma. We first identified microRNAs that map within chromosomal regions that we and others have defined as frequently deleted (1p36, 3p22, and 11q23-24) or gained (17q23) in high-risk neuroblastoma. We then transiently transfected microRNA precursor mimics or inhibitors into a panel of six neuroblastoma cell lines that we characterized for these genomic aberrations. The majority of transfections showed no phenotypic effect, but the miR-34a (1p36) and miR-34c (11q23) mimics showed dramatic growth inhibition in cell lines with 1p36 hemizygous deletion. In contrast, there was no growth inhibition by these mimics in cell lines without 1p36 deletions. Quantitative reverse transcription-PCR showed a perfect correlation of absent miR-34a expression in cell lines with a 1p36 aberration and phenotypic effect after mimetic add-back. Expression of miR-34a was also decreased in primary tumors (n = 54) with 1p36 deletion (P = 0.009), but no mutations were discovered in resequencing of the miR-34a locus in 30 neuroblastoma cell lines. Flow cytometric time series analyses showed that the likely mechanism of miR-34a growth inhibition is through cell cycle arrest followed by apoptosis. BCL2 and MYCN were identified as miR-34a targets and likely mediators of the tumor suppressor phenotypic effect. These data support miR-34a as a tumor suppressor gene in human neuroblastoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/genética , Neuroblastoma/metabolismo , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Deleção de Genes , Perfilação da Expressão Gênica , Genes bcl-2 , Humanos , MicroRNAs/metabolismo , MicroRNAs/fisiologia , RNA Interferente Pequeno/metabolismo , Fatores de Tempo
12.
Pediatr Blood Cancer ; 52(1): 44-50, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18937318

RESUMO

BACKGROUND: The components of therapy required for patients with INSS Stage 3 neuroblastoma and high-risk features remain controversial. PROCEDURE: A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG-3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 +/- 6% and 59 +/- 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5-year EFS of 65 +/- 11% and OS of 65 +/- 11% compared to 41 +/- 11 (P = 0.21) and 46 +/- 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13-cis-RA (n = 23) had 5-year EFS of 70 +/- 10% and OS of 78 +/- 9% compared to 63 +/- 12% (P = 0.67) and 67 +/- 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13-cis-RA (n = 6) had a 5-year EFS of 80 +/- 11% and OS of 100%. CONCLUSION: Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome.


Assuntos
Transplante de Medula Óssea/métodos , Isotretinoína/uso terapêutico , Neuroblastoma/terapia , Purging da Medula Óssea , Cisplatino , Terapia Combinada , Ciclofosfamida , Doxorrubicina , Etoposídeo , Humanos , Lactente , Neuroblastoma/mortalidade , Radioterapia , Risco , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
13.
N Engl J Med ; 353(21): 2243-53, 2005 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-16306521

RESUMO

BACKGROUND: Neuroblastoma is a childhood cancer with considerable morbidity and mortality. Tumor-derived biomarkers may improve risk stratification. METHODS: We screened 915 samples of neuroblastoma for loss of heterozygosity (LOH) at chromosome bands 1p36 and 11q23. Additional analyses identified a subgroup of cases of 11q23 LOH with unbalanced 11q LOH (unb11q LOH; defined as loss of 11q with retention of 11p). The associations of LOH with relapse and survival were determined. RESULTS: LOH at 1p36 was identified in 209 of 898 tumors (23 percent) and LOH at 11q23 in 307 of 913 (34 percent). Unb11q LOH was found in 151 of 307 tumors with 11q23 LOH (17 percent of the total cohort). There was a strong association of 1p36 LOH, 11q23 LOH, and unb11q LOH with most high-risk disease features (P<0.001). LOH at 1p36 was associated with amplification of the MYCN oncogene (P<0.001), but 11q23 LOH and unb11q LOH were not (P<0.001 and P=0.002, respectively). Cases with unb11q LOH were associated with three-year event-free and overall survival rates (+/-SE) of 50+/-5 percent and 66+/-5 percent, respectively, as compared with 74+/-2 percent and 83+/-2 percent among cases without unb11q LOH (P<0.001 for both comparisons). In a multivariate model, unb11q LOH was independently associated with decreased event-free survival (P=0.009) in the entire cohort, and both 1p36 LOH and unb11q LOH were independently associated with decreased progression-free survival in the subgroup of patients with features of low-risk and intermediate-risk disease (P=0.002 and P=0.02, respectively). CONCLUSIONS: Unb11q LOH and 1p36 LOH are independently associated with a worse outcome in patients with neuroblastoma.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 1/genética , Amplificação de Genes , Perda de Heterozigosidade , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Análise de Variância , Intervalo Livre de Doença , Seguimentos , Marcadores Genéticos , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/mortalidade , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida
14.
J Natl Cancer Inst ; 110(10): 1084-1093, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29514301

RESUMO

Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001). Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6 , Amplificação de Genes , Genômica , Neuroblastoma/genética , Neuroblastoma/mortalidade , Biomarcadores Tumorais , Pré-Escolar , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Genômica/métodos , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc/genética , Estadiamento de Neoplasias , Neuroblastoma/patologia , Neuroblastoma/terapia , Prognóstico
15.
Nat Commun ; 8(1): 569, 2017 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-28924153

RESUMO

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. Here we identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The association is replicated in 44 independent cases and 1902 controls. Our study yields novel insights into the genetic underpinnings of neuroblastoma, demonstrating that the inherited common variants reported contribute to the origin of intra-tumor genetic heterogeneity in neuroblastoma.Chromosomal abnormalities such as 11q deletion are associated with poor prognosis in neuroblastoma. Here, the authors perform a genome-wide association study and identify an association between a variant within a Matrix metalloproteinase (MMP) gene member, MMP20, and 11q-deletion subtype neuroblastoma.


Assuntos
Deleção Cromossômica , Metaloproteinase 20 da Matriz/genética , Neuroblastoma/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 11 , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas , Sequenciamento do Exoma
16.
Clin Cancer Res ; 21(8): 1782-5, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25424848

RESUMO

Utilizing genomic signatures from diagnostic tumor samples to forecast clinical behavior and response to therapy has long been a goal, and we are now poised to further refine how we can identify the relatively rare patients with aggressive neuroblastoma masquerading as patients with a more benign form of the disease. Clin Cancer Res; 21(8); 1782-5. ©2014 AACR. See related article by Oberthuer et al., p. 1904.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neuroblastoma/genética , Neuroblastoma/mortalidade , Feminino , Humanos , Masculino
17.
Cancer Genet ; 208(7-8): 408-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26163103

RESUMO

Copy number alterations (CNAs) are a hallmark of pediatric cancer genomes. An increasing number of research groups use multiple platforms and software packages to detect and analyze CNAs. However, different platforms have experimental and analysis-specific biases that may yield different results. We sought to estimate the concordance of CNAs in children with de novo acute myeloid leukemia between two experimental platforms: Affymetrix SNP 6.0 array and Illumina OmniQuad 2.5 BeadChip. Forty-five paired tumor-remission samples were genotyped on both platforms, and CNAs were estimated from total signal intensity and allelic contrast values using the allele-specific copy number analysis of tumors (ASCAT) algorithm. The two platforms were comparable in detection of CNAs, each missing only two segments from a total of 42 CNAs (4.6%). Overall, there was an interplatform agreement of 96% for allele-specific tumor profiles. However, poor quality samples with low signal/noise ratios showed a high rate of false-positive segments independent of the genotyping platform. These results demonstrate that a common analytic pipeline can be utilized for SNP array data from these two platforms. The customized programming template for the preprocessing, data integration, and analysis is publicly available at https://github.com/AplenCHOP/affyLumCNA.


Assuntos
Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Leucemia Mieloide/genética , Perda de Heterozigosidade , Doença Aguda , Feminino , Genótipo , Humanos , Masculino , Análise em Microsséries/métodos , Polimorfismo de Nucleotídeo Único
18.
Oncotarget ; 6(21): 18558-76, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26053094

RESUMO

Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Interferência de RNA , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/genética , Criança , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , Mutação , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Transplante Heterólogo , Carga Tumoral/genética
19.
Cancer Cell ; 28(5): 599-609, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26481147

RESUMO

A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting.


Assuntos
Aurora Quinase A/genética , Neuroblastoma/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Proteína ran de Ligação ao GTP/genética , Aurora Quinase A/metabolismo , Western Blotting , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Cromossomos Humanos Par 12/genética , Variações do Número de Cópias de DNA , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína ran de Ligação ao GTP/metabolismo
20.
Nat Genet ; 47(8): 864-71, 2015 08.
Artigo em Inglês | MEDLINE | ID: mdl-26121087

RESUMO

The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.


Assuntos
Sistema de Sinalização das MAP Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Recidiva Local de Neoplasia/genética , Neuroblastoma/genética , Proteínas ras/genética , Quinase do Linfoma Anaplásico , Animais , Benzimidazóis/farmacologia , Western Blotting , Linhagem Celular Tumoral , Criança , Pré-Escolar , Aberrações Cromossômicas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Lactente , Masculino , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Fosforilação/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
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