Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors

Xuexia Wang, Purnima Singh, Liting Zhou, Noha Sharafeldin, Wendy Landier, Lindsey Hageman, Paul Burridge, Yutaka Yasui, Yadav Sapkota, Javier G. Blanco, Kevin C. Oeffinger, Melissa M. Hudson, Eric J. Chow, Saro H. Armenian, Joseph P. Neglia, A. Kim Ritchey, Douglas S. Hawkins, Jill P. Ginsberg, Leslie L. Robison, Gregory T. ArmstrongSmita Bhatia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


PURPOSEInterindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication).METHODSA genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1.RESULTSTwo SNPs (rs17736312 [ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect (TGF-β1, P =.007); gene*anthracycline interaction (ROBO2*anthracycline, P =.0003); and gene*gene*anthracycline interaction (SLIT2*TGF-β1*anthracycline, P =.009).CONCLUSIONThese findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 (ROBO2) and anthracycline-related cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1758-1769
Number of pages12
JournalJournal of Clinical Oncology
Issue number9
StatePublished - Mar 20 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors'. Together they form a unique fingerprint.

Cite this