title: Expression of two parental imprinted miRNAs improves the risk stratification of neuroblastoma patients.
abstract: Age at diagnosis, stage, and MYCN amplification are the cornerstones of the risk-stratification score of neuroblastoma that enables defining patients at low- and high risk. Refinement of this stratification is needed to optimize standard treatment and to plan future clinical trials. We investigated whether two parental imprinted miRNAs (miR-487b and miR-516a-5p) may lead to a risk score with a better discrimination. Expression levels of maternal miR-487b and paternal miR-516a-5p were determined using quantitative RT-PCR both for 231 neuroblastoma tumors (derivation set) and 101 independent neuroblastoma tumors (validation set). Survival outcomes were overall survival (OS) and disease-free survival (DFS). Multivariable Cox models were developed from derivation set and their performance evaluated using Akaike's information criterion (AIC) (goodness-of-fit) and time-dependent area under curves (discrimination). The selected model was validated using internal and external validation. The prognostic model including current prognostic factors plus miR-487b, miR-516a-5p, and interaction between two miRNAs was selected. Performance of this model was better in terms of both predictive ability (smallest AIC) and discrimination power (AUC close to 0.70). This model identifies three risk groups: high (3), intermediate (2), and low (1). Hazard ratios (HR) across risk groups were HR2/1 = 6.3 (2.7-14.6), HR3/1 = 14.8 (7.2-30.2) for OS and HR2/1 = 2.8 (1.5-5.4), HR3/1 = 7.2 (3.9-13.4) for DFS. The rank between these three risk groups was maintained and validated when performing internal and external validation. Expression of maternal miR-487b and paternal miR-516a-5p improves the risk stratification. This better discrimination at diagnosis is of clinical utility both for current and future treatments of neuroblastoma patients.
authors.affiliation: CNRS UMR 8126, Université Paris-Sud, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France; INSERM UMR 1078, Etablissement Français du Sang, Centre Hospitalier Régional Universitaire de Brest, SFR ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 avenue Camille Desmoulins, 29200, Brest, France.
authors.forename: Charles-Henry
authors.initials: CH
authors.lastname: Gattolliat
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Le Teuff
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Eugénie
authors.initials: E
authors.lastname: Mussard
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.forename: Sétha
authors.initials: S
authors.lastname: Douc-Rasy
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; C568526:MIRN487 microRNA, human; C557718:MIRN516 microRNA, human; D035683:MicroRNAs
keywords: miRNA clusters; neuroblastoma; parental imprinting; prognostic model; risk score; survival outcomes