Apoptosis pathway signature for prediction of treatment response and clinical outcome in childhood high risk B-Precursor acute lymphoblastic leukemia

The most common cancer in children is acute lymphoblastic leukemia (ALL) and it had high cure rate, especially for B-precursor ALL. However, relapse due to drug resistance and overdose treatment reach the limitations in patient managements. In this study, integration of gene expression microarray data, logistic regression, analysis of microarray (SAM) method, and gene set analysis were performed to discover treatment response associated pathway-based signatures in the original cohort. Results showed that 3772 probes were significantly associated with treatment response. After pathway analysis, only apoptosis pathway had significant association with treatment response. Apoptosis pathway signature (APS) derived from 15 significantly expressed genes had 88% accuracy for treatment response prediction. The APS was further validated in two independent cohorts. Results also showed that APS was significantly associated with induction failure time (adjusted hazard ratio [HR] = 1.60, 95% confidence interval [CI] = [1.13, 2.27]) in the first cohort and significantly associated with event-free survival (adjusted HR = 1.56, 95% CI = [1.13, 2.16]) or overall survival in the second cohort (adjusted HR = 1.74, 95% CI = [1.24, 2.45]). APS not only can predict clinical outcome, but also provide molecular guidance of patient management.