Abstract 4664: Differential transcript usage reveals SERINC2 as a prognostic biomarker in clear cell renal cell carcinoma (ccRCC)

Abstract Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, accounts for approximately 75% of cases1. While differentially expressed gene (DEG) analyses have provided valuable insights, they often neglect alternative splicing (AS), a key driver of transcriptome diversity and functional protein complexity. AS is essential in modulating tumor biology and can impact disease progression and survival outcomes2. To address this gap, we performed a differential transcript usage (DTU) analysis in ccRCC to explore the role of AS in shaping survival-associated signatures. Methods: A total of 172 tumor samples from the Dartmouth Renal Tumor Biobank were analyzed. Following quality control, transcripts expressed in > 0.1 TPM in at least 25% of tumor samples were retained, yielding 31,850 transcripts. DTU was assessed using DRIMSeq, while functionality was evaluated with IsoformSwitchAnalyzeR. Cox proportional hazards analysis and machine learning-based Cox-LASSO regression was applied to identify survival-associated features, followed by log-rank analysis to explore their prognostic relevance. Results: DTU analysis revealed significant transcript-level changes linked to survival outcomes. Among these, SERINC2 emerged as the most statistically significant survival-associated gene, with its transcript NM_001199039.2 exhibiting a hazard ratio (HR) of 0.5 (95% CI: 0.39-0.69). Kaplan-Meier analysis confirmed that elevated expression levels of this transcript were significantly associated with better survival outcomes (p < 0.05). SERINC2 is linked to membrane lipid synthesis and may be associated with lipid metabolic reprogramming, a hallmark of ccRCC pathogenesis. Notably, isoform NM_001199039.2 has the shortest N-terminus regions compared to other validated isoforms, possibly conferring unique functionality. Finally, a prognostic model based on the Cox model demonstrated AUC values of 0.68 for 3-year survival and 0.78 for 5-year survival, indicating strong predictive potential for long-term outcomes. Conclusions: Our findings identify the SERINC2 splice variant (variant 5), NM_001199039.2, as a potential biomarker for favorable outcomes. We will conduct further validation in independent datasets and experimental systems to delineate the role of this splice variant on survival outcomes in ccRCC. References. 1. Jonasch E, Walker CL, et al. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17(4):245-261. doi:10.1038/s41581-020-00359-22. Marques-Coelho D, Iohan L da CC, Melo de Farias AR, et al. Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains. NPJ Aging Mech Dis. 2021;7(1). doi:10.1038/s41514-020-00052-5 Citation Format: Chinaza Nnam, Minghui Zhang, Brock Christensen, Lucas Salas. Differential transcript usage reveals SERINC2 as a prognostic biomarker in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4664.