ROBO2 as a Novel Susceptibility Gene for Risk of Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors

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In a study reported in the Journal of Clinical Oncology, Wang et al found that a single-nucleotide polymorphism (SNP) in ROBO2 was associated with an increased risk of cardiomyopathy among childhood cancer survivors receiving higher cumulative anthracycline doses.

As stated by the investigators, “Interindividual 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 (CCSS; discovery cohort) and the Children’s Oncology Group (COG) study COG-ALTE03N1 (replication cohort).”

Study Details

The study included genome-wide association analysis in 1,866 anthracycline-exposed CCSS patients, including 126 with heart failure, to identify SNPs with main or gene-environment interaction effects on anthracycline-related cardiomyopathy. Replication of findings was attempted in a matched case-control cohort of anthracycline-exposed survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1.

Key Findings

In the discovery cohort, two SNPs, consisting of rs17736312 in ROBO2 and rs113230990 (non-ROBO2) met the significance cutoff for gene-anthracycline dose interaction. The significance of only SNP rs17736312 in ROBO2 was maintained in the replication cohort.

Compared with rs17736312 GG/AG genotypes and cumulative anthracycline dose of ≤ 250 mg/m2, the AA genotype and anthracycline dose > 250 mg/m2 was associated with significantly increased risk of cardiomyopathy in the discovery cohort (odds ratio [OR] = 2.2, 95% confidence interval [CI] =1.2–4.0, P = .009) and in the replication cohort (OR = 8.2, 95% CI = 2.0–34.4, P = .004). Among patients with anthracycline exposure ≤ 250 mg/m2, those with the AA genotypes had a higher risk of cardiomyopathy vs those with GG/AG genotypes in the discovery cohort (OR = 1.8, 95% CI = 1.1–2.9, P = .02) and replication cohort (OR = 2.96, 95% CI = 1.1–7.7, P = .03).

As stated by the investigators, “ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). [The] Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1 [TGF-β1]/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure.” In evaluation in the CCSS cohort, significant gene-level associations with cardiomyopathy were identified, consisting of TGF-β1 (P = .007) for main effect, ROBO2*anthracycline (P = .0003) for gene*anthracycline interaction, and SLIT2*TGF-β1*anthracycline (P = .009) for gene*gene*anthracycline interaction.

The investigators concluded, “These 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.”

Smita Bhatia, MD, MPH, of the University of Alabama at Birmingham, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Leukemia & Lymphoma Society, National Cancer Institute, St. Baldrick’s Foundation, and others. For full disclosures of the study authors, visit


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