Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

Purnima Singh, Disheet A. Shah, Mariam Jouni, Romina B. Cejas, David K. Crossman, Tarek Magdy, Shaowei Qiu, Xuexia Wang, Liting Zhou, Noha Sharafeldin, Lindsey Hageman, Donald E. McKenna, Saro H. Armenian, Frank M. Balis, Douglas S. Hawkins, Frank G. Keller, Melissa M. Hudson, Joseph P. Neglia, A. Kim Ritchey, Jill P. GinsbergWendy Landier, Ravi Bhatia, Paul W. Burridge, Smita Bhatia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. METHODS AND RESULTS: We designed a matched case-control study (Children’s Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/ Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. CONCLUSIONS: We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Original languageEnglish (US)
Article numbere029954
JournalJournal of the American Heart Association
Volume12
Issue number19
DOIs
StatePublished - Oct 3 2023

Keywords

  • anthracyclines
  • cardiomyopathy
  • childhood cancer survivors
  • gene expression
  • peripheral blood
  • transcriptome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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