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

Wang X, Singh P, Zhou L, Sharafeldin N, Landier W, Hageman L, Burridge P, Yasui Y, Sapkota Y, Blanco JG, Oeffinger KC, Hudson MM, Chow EJ, Armenian SH, Neglia JP, Ritchey AK, Hawkins DS, Ginsberg JP, Robison LL, Armstrong GT, Bhatia S. Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors. J Clin Oncol. 2023 Mar 20;41(9):1758-1769. doi: 10.1200/JCO.22.01527. Epub 2022 Dec 12. PubMed PMID: 36508697; PubMed Central PMCID: PMC10043563.

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 (discovery) and the Children’s Oncology Group (COG) study COG-ALTE03N1 (replication). A 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.