MicroRNA-Gene Association As a Prognostic Biomarker in Cancer Exposes Disease Mechanisms

Rotem Ben-Hamo, Sol Efroni

The transcriptional networks that regulate gene expression and modifications to this network are at the core of the cancer phenotype. MicroRNAs, a well-studied species of small non-coding RNA molecules, have been shown to have a central role in regulating gene expression as part of this transcriptional network. Further, microRNA deregulation is associated with cancer development and with tumor progression. Glioblastoma Multiform (GBM) is the most common, aggressive and malignant primary tumor of the brain and is associated with one of the worst 5-year survival rates among all human cancers. To study the transcriptional network and its modifications in GBM, we utilized gene expression, microRNA sequencing, whole genome sequencing and clinical data from hundreds of patients from different datasets. Using these data and a novel microRNA-gene association approach we introduce, we have identified unique microRNAs and their associated genes. This unique behavior is composed of the ability of the quantifiable association of the microRNA and the gene expression levels, which we show stratify patients into clinical subgroups of high statistical significance. Importantly, this stratification goes unobserved by other methods and is not affiliated by other subsets or phenotypes within the data. To investigate the robustness of the introduced approach, we demonstrate, in unrelated datasets, robustness of findings. Among the set of identified microRNA-gene associations, we closely study the example of MAF and hsa-miR-330-3p, and show how their co-behavior stratifies patients into prognosis clinical groups and how whole genome sequences tells us more about a specific genomic variation as a possible basis for patient variances. We argue that these identified associations may indicate previously unexplored specific disease control mechanisms and may be used as basis for further study and for possible therapeutic intervention.