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Abstract 4352: Genetic effects on gene expression and survival in patients with multiple myeloma

Multiple myeloma (MM) is the second most common hematological cancer, accounting for 2% of all cancer deaths. MM is associated with a poor prognosis, with a 5-year overall survival of 50.7%. While the introduction of new therapies in the last decade has nearly doubled the survival rate, most patients still experience a relapse. To this end, The Multiple Myeloma Research Foundation developed the CoMMpass study. CoMMpass is a longitudinal clinical trial aimed at accelerating the discovery of more targeted treatments for MM. Clinical parameters and tumor specimens are collected from each of the 1,147 patients at baseline and through the eight-year observation period. To identify genetic determinants of clinical outcomes, each tumor specimen is characterized by Whole Genome, Exome and Transcriptome sequencing. This work has uncovered a number of somatic mutations and copy number alterations associated with tumor progression and response to therapy as well as a novel classification of MM into 12 distinct subtypes based on gene expression. However, the contribution of germline genetic variation to gene expression changes and MM outcome remains poorly understood. Genome-wide association studies have identified germline variants associated with MM risk, indicating inherited genetic susceptibility. Furthermore, MM exhibits a disparity in occurrence and mortality between the sexes and ethnicities, men and African Americans being in at a higher risk than women or those of European ancestry. To better understand the genetic and biological basis of MM predisposition, we utilize a systems genomics approach to examine non-coding inherited and somatic genetic effects on gene expression and MM outcome. Data from 607 CoMMpass participants with available WGS and RNAseq from normal blood and baseline tumor specimens were used to map cis-acting eQTLs. We identified 3929 genes with at least one cis-acting eQTL. Furthermore, we discovered a number of regulatory variants with differential effects on tumor gene expression between the sexes and ethnicities, as well as eQTLs overlapping MM GWAS risk loci, providing regulatory mechanisms connecting these loci to MM. Finally, we discovered eQTLs that modulate overall survival in patients with MM. To validate these putatively regulatory loci in vitro, we utilized MM cell lines and CRISPR activation/interference, successfully altering the expression of the target genes. These and analyses integrating germline and somatic variants, gene expression, and clinical outcomes support the development of personalized medicine approaches for the better treatment of MM. Citation Format: Heini M. Natri, Austin Gutierrez, Bianca Argente, Melissa Wilson Sayres, Kenneth Buetow, Nicholas Banovich. Genetic effects on gene expression and survival in patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4352.