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Background <p>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.</p> Methods <p>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.</p> Results <p>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 <i>RPS24</i> and skipped exon of <i>PFND5</i> showed differential expression of altered transcripts.</p> Conclusions <p>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.</p> Graphical abstract <p>Central Illustration. Aberrant alternative splicing and anthracycline-induced cardiomyopathy. This study sought to identify alternative splice variants that are differentially abundant between anthracycline-exposed childhood cancer survivors that developed cardiomyopathy (cases) versus those who did not (controls). We observed dysregulated alternative splicing of <i>PFDN5</i> and <i>RPS24</i> is associated with the development of cardiomyopathy.Splicing defects in <i>PFDN5</i> impair cytoskeletal protein folding, while <i>RPS24</i> dysregulation affects their translation, disrupting actin and tubulin homeostasis. Together, these alterations destabilize cardiomyocyte structure, contributing to sarcomere disorganization and the development of cardiomyopathy. Created in BioRender. Singh, P. (2025) <a href="https://BioRender.com/59zmgls">https://BioRender.com/59zmgls</a>.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月17日

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  • Purnima Singh,
  • David K. Crossman,
  • Changde Cheng,
  • Patrick J. Trainor,
  • Noha Sharafeldin,
  • Xuexia Wang,
  • Liting Zhou,
  • Lindsey Hageman,
  • Saro H. Armenian,
  • Frank M. Balis,
  • Douglas S. Hawkins,
  • Frank G. Keller,
  • Melissa M. Hudson,
  • Joseph P. Neglia,
  • Jill P. Ginsberg,
  • Wendy Landier,
  • Smita Bhatia

摘要

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.

Graphical abstract

Central Illustration. Aberrant alternative splicing and anthracycline-induced cardiomyopathy. This study sought to identify alternative splice variants that are differentially abundant between anthracycline-exposed childhood cancer survivors that developed cardiomyopathy (cases) versus those who did not (controls). We observed dysregulated alternative splicing of PFDN5 and RPS24 is associated with the development of cardiomyopathy.Splicing defects in PFDN5 impair cytoskeletal protein folding, while RPS24 dysregulation affects their translation, disrupting actin and tubulin homeostasis. Together, these alterations destabilize cardiomyocyte structure, contributing to sarcomere disorganization and the development of cardiomyopathy. Created in BioRender. Singh, P. (2025) https://BioRender.com/59zmgls.