Development and validation of GMI signature based random survival forest prognosis model to predict clinical outcome in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a disease with marked molecular heterogeneity and a high early death rate. Our aim was to investigate an integrated Gene expression, Mirna and miRNA-mRNA Interactions (GMI) signature for improving risk stratification of AML. METHODS: We identified differentially expressed genes by pooling a large number of 861 human AML patients and 75 normal cases. We then used miRWalk to identify the functional miRNA-mRNA regulatory module. The GMI signature based random survival forest (RSF) prognosis model was developed from training data set and evaluated in independent patient cohorts from The Cancer Genome Atlas (TCGA) dataset (N = 147). Univariate and multivariate Cox proportional hazards regression analyses were applied to evaluate the prognostic value of GMI signature. RESULTS: We identified 139 differentially expressed genes between normal and abnormal AML samples. We discovered the functional miRNA-mRNA regulatory module which participate in the network of cancer progression. We named 23 differentially expressed genes and 16 validated target miRNAs as the GMI signature. The RSF model-based scores separated independent patient cohorts into two groups with significantly different overall survival (C-index = 0.59, hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.11-4.03; p = 0.019). Similar results were obtained with reversed training and testing datasets (C-index = 0.58, hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.02-4.24; p = 0.038). The GMI signature score contributed more information about recurrence than standard clinical covariates. CONCLUSION: The GMI signature based RSF prognosis model not only reflects regulatory relationships from identified miRNA-mRNA module but also informs patient prognosis. While in the TCGA data set the GMI signature score contributed additional information about recurrence in comparison to standard clinical covariates, further studies are needed to determine its clinical significance.