Improved risk stratification and outcome prediction in children with average risk 1 precursor-B acute lymphoblastic leukemia using a 19-microRNA signature

Background: Risk stratification has led to a tremendous improvement of the 5-year overall survival rates in childhood acute lymphoblastic leukemia (ALL). The average risk group 1 (AR1), consisting of all non-very low risk and non-very high risk B-cell lineage ALL patients, is the largest patient group accounting for 57% in our experience. Despite the good overall survival, the total number of relapses observed in this AR1 group is considerable. Aim: In this study, we aimed at identifying a marker able to predict relapse, at the stage of diagnosis. To this end, we focused on the recently discovered microRNAs of which their expression has been reported to hold prognostic power in other cancer types. Methods: A total of 693 microRNAs were profiled using automated high-throughput quantitative stem-loop RT-PCR in a cohort of diagnostic bone marrow samples from AR1 pediatric precursor B-cell ALL patients in continuous complete remission (follow-up>6 years) and patients who experienced relapse. All patients were treated according to the EORTC-CLG protocol 58951 (December 1998-August 2008). The ethical committee approved the study and informed consent was obtained from the patients and/or their parents. Statistics were performed using SPSS17 and R (Bioconductor). Results: Logistic regression analysis and Prediction Analysis of Microarray allowed us to identify a 19-microRNA signature, prognostic for relapse within this group. The signature has an accuracy, sensitivity and specificity of 77 %, 69 % and 84 %, respectively. Currently, the signature is evaluated in an independent validation cohort. Notably, several of the microRNAs present in this signature are known oncogenes or tumor suppressor genes. Multivariate analysis, including the microRNA signature, white blood cell count and age, shows that the 19-microRNA signature is an independent prognostic factor. Conclusions: The identified 19-microRNA signature is a unique and powerful tool for further risk-stratification. The method and signature are suitable for routine laboratory testing and will be further evaluated in a prospective study