Gene Co-expression Network and Copy Number Variation Analyses Identify Transcription Factors Associated With Multiple Myeloma Progression.

Christina Y Yu,Mohammad Abu Zaid,Shunian Xiang,Xiaohui Zhan,Travis S Johnson,Zhi Han,Zhi Huang,Kun Huang

doi:10.3389/fgene.2019.00468

Abstract

Multiple myeloma (MM) has two clinical precursor stages of disease: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the mechanism of progression is not well understood. Because gene co-expression network analysis is a well-known method for discovering new gene functions and regulatory relationships, we utilized this framework to conduct differential co-expression analysis to identify interesting transcription factors (TFs) in two publicly available datasets. We then used copy number variation (CNV) data from a third public dataset to validate these TFs. First, we identified co-expressed gene modules in two publicly available datasets each containing three conditions: normal, MGUS, and SMM. These modules were assessed for condition-specific gene expression, and then enrichment analysis was conducted on condition-specific modules to identify their biological function and upstream TFs. TFs were assessed for differential gene expression between normal and MM precursors, then validated with CNV analysis to identify candidate genes. Functional enrichment analysis reaffirmed known functional categories in MM pathology, the main one relating to immune function. Enrichment analysis revealed a handful of differentially expressed TFs between normal and either MGUS or SMM in gene expression and/or CNV. Overall, we identified four genes of interest (MAX, TCF4, ZNF148, and ZNF281) that aid in our understanding of MM initiation and progression.

Highlights

Multiple myeloma (MM) is a B-cell malignancy caused by the proliferation of aberrant clonal plasma cells that secrete monoclonal immunoglobulin protein, known as M protein
There is an intermediate precursor between monoclonal gammopathy of undetermined significance (MGUS) and MM known as smoldering multiple myeloma (SMM)
We validated our transcription factors (TFs) with copy number variation (CNV) data taken from a third publicly available dataset, looking for genes located on chromosomal segments that showed a consistent trend in aberration from normal to SMM and identified four TFs: MAX, ZNF148, TCF4, and ZNF281

Summary

Introduction

Multiple myeloma (MM) is a B-cell malignancy caused by the proliferation of aberrant clonal plasma cells that secrete monoclonal immunoglobulin protein, known as M protein. An individual with MGUS lives with an increased risk of developing MM at a rate of 1% per year (Kyle et al, 2002). There is an intermediate precursor between MGUS and MM known as smoldering multiple myeloma (SMM). This phase is clinically defined by a higher threshold in M-protein or clonal bone marrow plasma cell content with the continued absence of CRAB features (Rajkumar et al, 2014). The risk of progression for SMM increases at a variable rate, as 10% per year for the first 5 years, 3% per year for the 5 years, and 1% per year in the following 10 years (Kyle et al, 2007). Understanding the biological basis of MM progression from these precursors is still unclear

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