Neuroblastoma mRNAs Predict Outcome in Children With Stage 4 Neuroblastoma: A European HR-NBL1/SIOPEN Study

Viprey, Virginie; Gregory, Walter M.; Corrias, Maria Valeria; Tchirkov, Andréï; Swerts, Katrien; Vícha, Aleš; Dallorso, Sandro; Brock, Pénélope; Luksch, Roberto; Valteau‐Couanet, Dominique; Papadakis, Vassilios; Laureys, Geneviève; Pearson, Andrew D.J.; Ladenstein, Ruth; Burchill, Susan A.

doi:10.1200/jco.2013.53.3604

Cited by 103 publications

(147 citation statements)

References 32 publications

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“…However, our study showed that outcomes within the high-risk group differ according to TH expression in PB at diagnosis. Previous studies also reported that positive TH expression was a poor prognostic indicator in metastatic NB [13,21,22]. These findings suggest that TH expression at diagnosis might be a significant factor in future methods of risk stratification for NB.…”

Section: Discussionsupporting

confidence: 56%

“…These ultrahigh-risk patients showed very poor outcome among the group of high-risk NB patients (PFS, 0%), most of whom underwent single HDCT/auto-SCT following short induction treatment. The authors suggested that patients with very high TH expression are candidates for alternative treatment strategies [22]. In the current study, the prognosis of patients with high TH expression was also poorer than for those with low TH expression, but was not dismal.…”

Section: Discussionmentioning

confidence: 48%

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Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma

et al. 2016

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PurposeThe purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma.Materials and MethodsTH mRNA expression in PB was measured by reverse transcription quantitative real-time polymerase chain reaction in 210 patients who were newly diagnosed with neuroblastoma from July 2005 to June 2015 and the clinical significance of TH expression in PB at diagnosis was evaluated.ResultsTH expression was positive in 60 patients (28.6%). Fifty of 60 TH-positive patients had metastatic tumors and the remaining 10 had localized tumors. TH expression was associated with high-risk features (i.e., advanced stage, older age, unfavorable pathology, and MYCN amplification) at diagnosis. Among TH-positive patients, higher TH expression level was observed in high-risk patients than in low- or intermediate-risk patients (p=0.035). The probability of 5-year progression-free survival (PFS) was lower in TH-positive patients than in TH-negative patients (63.8±6.9% vs. 94.7±2.1%, p < 0.001). In analysis confined to high-risk patients, the 5-year probability of PFS remained lower in TH-positive patients (55.7±8.2% vs. 89.6±5.8%, p < 0.001). Among TH-positive patients, a higher expression level of TH was associated with a worse outcome. In multivariate analyses, positive TH expression in PB at diagnosis was an independent poor prognostic factor for PFS.ConclusionThe treatment intensity should be tailored according to TH expression in PB at diagnosis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 48%

Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma

et al. 2016

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“…Here we show that mutations in FA and RAC pathways (promoting metastasis and cancer progression) occur frequently in a subset of unfavourable neuroblastoma and confirm this finding in three independent sets of neuroblastoma samples. A recent study has suggested that dysfunction of FA pathway promotes bone marrow infiltration of stage 4 neuroblastoma [2]. Importantly, anticancer compounds targeting FA and RAC pathways can reduce growth, motility and viability of tumor cells in neuroblastoma [37].…”

Section: Discussionmentioning

confidence: 99%

“…Although many low and intermediate-risk patients are amenable to no or little therapy, overall survival rates of patients diagnosed as high-risk tumors remain below 50% despite receiving complex and intensive treatments [1]. Among high-risk patients, gene signatures can identify children with higher risk disease who would benefit from new and more aggressive therapeutic approaches [2]. Genome-wide association studies have identified multiple DNA polymorphisms influencing neuroblastoma susceptibility and clinical phenotype [3-7].…”

Section: Introductionmentioning

confidence: 99%

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

et al. 2016

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The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

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“…In this regard, several mRNA and miRNA classifiers have been established [11-13]. A recent study from SIOPEN shows that levels of tyrosine hydroxylase ( TH ) and paired-like homeobox 2B ( PHOX2B ) or doublecortin ( DCX ) mRNA in peripheral blood and bone marrow at diagnosis are independent predictors of survival [14]. Notably, high levels of TH and PHOX2B mRNA in peripheral blood identify ultrahigh-risk NB patients.…”

Section: Introductionmentioning

confidence: 99%

Two independent epigenetic biomarkers predict survival in neuroblastoma

et al. 2015

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BackgroundNeuroblastoma (NB) is the most common extracranial pediatric solid tumor with a highly variable clinical course, ranging from spontaneous regression to life-threatening disease. Survival rates for high-risk NB patients remain disappointingly low despite multimodal treatment. Thus, there is an urgent clinical need for additional biomarkers to improve risk stratification, treatment management, and survival rates in children with aggressive NB.ResultsUsing gene promoter methylation analysis in 48 neuroblastoma tumors with microarray technology, we found a strong association between survival and gene promoter hypermethylation (P = 0.036). Hypermethylation of 70 genes significantly differentiated high-risk survivor patients from those who died during follow-up time. Sixteen genes with relevant roles in cancer biology were further validated in an additional cohort of 83 neuroblastoma tumors by bisulfite pyrosequencing. High promoter methylation rates of these genes were found in patients with metastatic tumors (either stage metastatic (M) or metastatic special (MS)), 18 months or older at first diagnosis, MYCN amplification, relapsed, and dead. Notably, the degree of methylation of retinoblastoma 1 (RB1) and teratocarcinoma-derived growth factor 1 (TDGF1) predicts event-free and overall survival independently of the established risk factors. In addition, low RB1 mRNA expression levels associate with poor prognosis suggesting that promoter methylation could contribute to the transcriptional silencing of this gene in NB.ConclusionsWe found a new epigenetic signature predictive for NB patients’ outcome: the methylation status of RB1 and TDGF1 associate with poorer survival. This information is useful to assess prognosis and improve treatment selection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0054-8) contains supplementary material, which is available to authorized users.

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Neuroblastoma mRNAs Predict Outcome in Children With Stage 4 Neuroblastoma: A European HR-NBL1/SIOPEN Study

Cited by 103 publications

References 32 publications

Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma

Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

Two independent epigenetic biomarkers predict survival in neuroblastoma

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