Studying Evolution of Multiple Myeloma with CanEvolve

Abstract 2886

Multiple Myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS), its pre-malignant stage at the rate of 1% per year. Moreover all MM patients eventually develop drug resistance. Currently, very little is known about this process of MM evolution, specifically about the changes in regulatory networks and signaling pathways responsible for it. One major difficulty in studying this is the lack of suitable functional genomics profiles covering all the stages of MM evolution from the same patients.

We have now modeled this process using the knowledge stored in the canEvolve portal for cancer integrative genomics and evolution (available at http://www.canevolve.org). The current version of the portal stores gene and miRNA expression and copy number alterations information derived from microarray and next generation sequencing platforms for more than 10 cancer types. It also stores hundreds of thousands of instances of protein-protein interactions, and metabolic and signaling pathway information for the Human proteome. The primary analysis capabilities include identification of differential gene expression, survival analysis and reconstructed gene regulatory networks and their visualization. Finally, canEvolve stores integrative analysis carried out using Gene set enrichment (GSEA) and GemiNI.

We carried out meta analysis of gene expression profiles of MGUS, smoldering Myeloma, MM and relapsed patients publicly available from multiple Gene expression omnibus (GEO) datasets. We carried out geneset enrichment analysis of normal-MGUS, normal-MM, normal-relapsed, MGUS-SMM, MGUS-MM and MM-relapsed pairs with different gene sets available from MSigDB. We identified transcription factors, miRNA, metabolic and signaling pathways whose targets/members significantly change expression. For example, targets of mir-17 and NF-Kappa B significantly change as MGUS turns to MM. Similarly, targets of miR-484 and CREL significantly changes as MM patients relapse. The CanEvolve portal thus provides us the ability to serially monitor and analyze various genomic datasets to provide targets that may play a crucial role in myelomagenesis as well as propgression of the disease. We are now validating some of the identified targets.