Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study.

Abstract

PURPOSE:

To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk.

METHODS:

RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy.

RESULTS:

High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value.

CONCLUSION:

High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.

• Authors: Virginie F Viprey, Walter M Gregory, Maria V Corrias, Andrei Tchirkov, Katrien Swerts, Ales Vicha, Sandro Dallorso, Penelope Brock, Roberto Luksch, Dominique Valteau-Couanet, Vassilios Papadakis, Genevieve Laureys, Andrew D Pearson, Ruth Ladenstein, Susan A Burchill
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 32 Issue 10 Pg. 1074-83 (Apr 01 2014) ISSN: 1527-7755 [Electronic] United States
• PMID: 24590653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• DCX protein, human
• Doublecortin Domain Proteins
• Doublecortin Protein
• Homeodomain Proteins
• Microtubule-Associated Proteins
• NBPhox protein
• Neuropeptides
• RNA, Messenger
• Transcription Factors
• Vincristine
• Etoposide
• Cyclophosphamide
• Carboplatin
• Tyrosine 3-Monooxygenase
• Cisplatin

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (blood, metabolism)
• Bone Marrow (metabolism)
• Carboplatin (administration & dosage)
• Child
• Child, Preschool
• Cisplatin (administration & dosage)
• Computer Simulation
• Cyclophosphamide (administration & dosage)
• Disease-Free Survival
• Doublecortin Domain Proteins
• Doublecortin Protein
• Etoposide (administration & dosage)
• Homeodomain Proteins (genetics)
• Humans
• Induction Chemotherapy
• Infant
• Kaplan-Meier Estimate
• Microtubule-Associated Proteins (genetics)
• Neuroblastoma (drug therapy, genetics, metabolism)
• Neuropeptides (genetics)
• Predictive Value of Tests
• Proportional Hazards Models
• RNA, Messenger (blood)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Transcription Factors (genetics)
• Tyrosine 3-Monooxygenase (genetics)
• Vincristine (administration & dosage)