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

Abstract

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.