Alternative mRNA splicing in anthracycline-induced cardiomyopathy – a COG-ALTE03N1 report

Background: Anthracycline-induced cardiomyopathy is a well-established adverse consequence in childhood cancer survivors. Altered mRNA expression in the peripheral blood has been found at the level of genes and pathways among anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. However, the role of aberrant alternative splicing in anthracycline-induced cardiomyopathy remains unexplored. The present study examined if transcript-specific events, due to alternative splicing occur in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods: Participants were anthracycline-exposed childhood cancer survivors with cardiomyopathy (cases) matched with anthracycline-exposed childhood cancer survivors without cardiomyopathy (controls; matched on primary cancer diagnosis, year of diagnosis, and race/ethnicity). mRNA sequencing was performed on total RNA from peripheral blood in 32 cases and 32 matched controls. Event-level splicing tool, rMATS (replicate Multivariate Analysis of Transcript Splicing) was used for quantitative profiling of alternative splicing events. Results: A total of 45 alternative splicing events in 36 genes were identified. Using a prioritization strategy to filter the alternative splicing events, intron retention in RPS24 and skipped exon of PFND5 showed differential expression of altered transcripts. Conclusions: We identified specific alternative splicing events in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Our findings suggest that differential alternative splicing events can provide additional insight into the peripheral blood transcriptomic landscape of anthracycline-induced cardiomyopathy.