Coordinated expression of retained introns and poison exons in renal cell carcinoma.

The regulation and impact of tumor-specific isoforms in cancer is challenging to understand, with unclear links between oncogenic signaling and mRNA processing and decay. Using transcriptomic analyses and experimental validation, we demonstrate that clear cell renal cell carcinoma (ccRCC) tumors exhibit coordinated intron retention (IR) and poison exon (PE) inclusion, generating transcripts targeted by nonsense-mediated decay (NMD). ccRCC tumors segregate into two subtypes based on IR: tumors with low IR levels and those with high IR levels, the latter associated with aggressive clinical features and poorer survival. We identify mammalian target of rapamycin (mTOR) signaling as a key modulator of IR and PE inclusion, showing mTOR inhibition significantly increases NMD-targeted isoforms, linking mTOR signaling with RNA surveillance pathways. Additionally, tumors with high IR levels exhibit increased T cell infiltration signatures. Collectively, these findings reveal a mechanism by which aggressive ccRCC tumors sustain aberrant RNA isoforms, offering insights for biomarker and therapeutic development.