Epigenome-Wide Association Studies of Proteasome Inhibitor-Related Cardiotoxicity in Patients with Multiple Myeloma

Area of Science:

• Genomics and Epigenetics
• Oncology
• Cardiology

Background:

• Proteasome inhibitors like carfilzomib (CFZ) and bortezomib (BTZ) are first-line treatments for relapsed/refractory multiple myeloma (MM).
• These therapies are associated with significant cardiovascular adverse events (CVAEs).
• Understanding the molecular basis of CVAEs is crucial for patient safety.

Purpose of the Study:

• To identify differentially methylated positions (DMPs) and regions (DMRs) associated with CVAEs in MM patients undergoing CFZ or BTZ treatment.
• To explore enriched biological pathways implicated in treatment-related CVAEs.
• To investigate potential epigenetic contributors to CVAEs in proteasome inhibitor therapy.

Main Methods:

• Analysis of baseline germline DNA methylation profiles from 79 MM patients in the PROTECT study.
• Epigenome-wide association studies (EWAS) were conducted separately for CFZ and BTZ treatment groups.
• Meta-analysis was performed to identify common epigenetic signals associated with CVAEs across both drug treatments.

Main Results:

• Four significant DMPs were associated with CFZ-related CVAEs, including those near ENSG00000224400, TBX3, and WDR86.
• One significant DMR was identified in the FAM166B region for CFZ-CVAEs.
• Suggestive DMPs and a DMR were noted in BTZ-treated patients (DNAJC18, USP18, WDR86/WDR86-AS1), but meta-analysis revealed no significant common DMPs.
• Pathway analysis implicated peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone signaling in CVAEs.

Conclusions:

• Distinct epigenetic signatures (DMPs and DMRs) are associated with CVAEs in patients treated with CFZ and, to a lesser extent, BTZ.
• Enriched pathways suggest diverse biological mechanisms underlying CVAEs.
• These findings highlight the role of epigenetics in CVAE development and underscore the need for larger validation studies.