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Genetic Factors Associated with Anthracycline-Induced Cardiomyopathy (COG-ALTE03N1)

We investigated the genetic mechanisms underlying anthracycline-induced cardiomyopathy, a serious long-term complication among childhood cancer survivors. We focused on the role of DNA damage response and repair (DDR) genes, which had not been previously studied in this context. A gene-based and pathway-based approach was applied to assess both the main effects and gene-by-anthracycline interaction effects of DDR genes on cardiomyopathy risk. The analysis was conducted using a matched case-control design within the COG-ALTE03N1 study, including 113 cases and 226 controls, all of whom were non-Hispanic White childhood cancer survivors exposed to anthracyclines. For each case, we randomly selected 1-3 childhood cancer survivors with no cardiomyopathy, matched on primary cancer diagnosis, year of diagnosis (±10y), and race/ethnicity. The selected controls had to have a longer duration of follow-up compared with time from cancer diagnosis to cardiomyopathy for the corresponding case.

Participants provided blood or saliva for germline DNA isolation and genotyping. Genotyping was performed using Illumina HumanOmniExpress-12 v1.0 (709,358 SNPs) and IlluminaOmni5Exome-4 v1.3 arrays (4,293,368 SNPs), with merging of genotype data from the two arrays (683,781 overlapped SNPs) and quality control (QC) using PLINK. Of the 220 genes in the MD Anderson DDR gene website, 187 genes with 2,220 single nucleotide polymorphisms [SNPs] identified on our array data were included in the analyses. A total of 2,170 SNPs were retained in the final gene-based and pathway-based analysis in 339 anthracycline-exposed non-Hispanic White (NHW) patients (113 cases; 226 controls). Key findings included significant associations for FANCC and XRCC5 with cardiomyopathy risk (main effect), and a significant gene-environment interaction involving MGMT. The study also confirmed the involvement of DDR-related biological pathways through both genetic association and interaction analyses.

Data Available Through dbGaP:

• Genotype data (GWAS) for all study participants

• Phenotype data: age at primary cancer diagnosis, sex, race/ethnicity, case-control status

This dataset supports further research into genetic susceptibility to chemotherapy-induced adverse outcomes and enables cross-cohort comparisons in cardio-oncology.