Document Type : Original Article(s)

Authors

• Zohreh Mehmandoostli ^{1, 2}
• Mahmood Dehghani Ashkezari ^{1, 2}
• Seyed Morteza Seifati ^{1, 2}
• Gholam Ali Kardar ^{3, 4}

¹ Department of Biology, Ashk.C., Islamic Azad University, Ashkezar, Iran

² Medical Biotechnology Research Center, Ashk.C., Islamic Azad University, Ashkezar, Iran

³ Immunology, Asthma and Allergy Research Institute (IAARI), Tehran University of Medical Sciences, Tehran, Iran

⁴ Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Renal cell carcinoma (RCC) is a heterogeneous malignancy with variable outcomes and limited biomarkers for prognosis or immunotherapy response. Although mutations in VHL, SETD2, PBRM1, BAP1, FLCN, and TP53 are frequent, their integrated effects on tumor biology, RNA editing, and non-coding RNA regulation remain unclear. This study aims to integrate genetic, epigenetic, and immune features to provide mechanistic insights into RCC progression and support precision immuno-oncology and vaccine development.
Methods: Transcriptomic data from TCGA-KIRC and four Gene Expression Omnibus (GEO) cohorts were normalized, batch-corrected, and integrated. Differentially expressed genes were analyzed using LASSO-Cox regression, Kaplan–Meier survival, ROC curves, and nomogram modeling. RNA editing events from REDIportal were annotated for nonsynonymous substitutions and assessed for human leukocyte antigen (HLA) class I binding. Parallel miRNA–mRNA analyses identified regulatory interactions. Functional enrichment and immune LASSO deconvolution were used to explore pathways and tumor microenvironment features.
Results: VHL, SETD2, and BAP1 were downregulated, while FLCN showed heterogeneous upregulation. A six-gene prognostic signature (BAP1, SETD2, TP53, PBRM1, FLCN, VHL) stratified patients into high- and low-risk groups with AUCs>0.70 at 1, 3, and 5 years. RNA editing revealed 35 recurrent events, including 25 nonsynonymous substitutions in TP53, BAP1, and SETD2. Predicted neoantigens included both broadly presented and population-specific epitopes. Deregulated miRNAs highlighted post-transcriptional regulation influencing progression and immune evasion. Functional enrichment analysis implicated chromatin remodeling, metabolism, and immune regulation, while immune profiling linked BAP1 mutations with reduced NK/Treg infiltration and identified chromatin genes associated with endothelial and immune activity.
Conclusion: This integrative study identifies a six-gene signature, recurrent RNA editing–derived neoantigens, and miRNA networks in RCC. By connecting genomic, epigenetic, and immune features, it provides mechanistic insights into RCC progression and supports precision immuno-oncology and vaccine development.

Highlights

Zohreh Mehmandoostli (Google Scholar)
Gholam Ali Kardar (Google Scholar)

Keywords

• Carcinoma, renal cell
• RNA editing
• Biomarkers
• Prognosis
• Antigens