Abstract B024: A mitochondrial plasma proteomic signature identifies metastatic chromophobe RCC

Abstract Background: Chromophobe renal cell carcinoma (ChRCC) is distinguished by the accumulation of morphologically abnormal mitochondrial accumulation, a high rate of mitochondrial DNA mutations (ND4 and ND5), and altered oxidative metabolism. There are no existing circulating biomarkers that can distinguish metastatic ChRCC from clear cell renal cell carcinoma (ccRCC). Methods: We performed high-throughput plasma proteomic profiling using the SomaScan platform in 18 ChRCC and 197 ccRCC patients. Data from the SomaScan 11K assay were harmonized with the 7K assay to generate a unified, cross-platform 7K-protein matrix. Differential expression analysis was conducted using limma. Results: Of 7,272 quantified human plasma proteins, 209 were differentially expressed in plasma between ChRCC and ccRCC (|log2FC| >= 1, FDR <= 0.05). Prominent upregulated proteins included essential β-oxidation enzymes such as ECH1, ACADVL, and ECI1, suggesting intensified long-chain fatty acid degradation. One-carbon metabolism and NADH-generating reactions were enriched, with increased expression of MTHFD2, MTHFD2L, SHMT2, FAHD1, and DLD. This metabolic configuration may reflect high demand for redox balance and mitochondrial respiration in ChRCC. Creatine and energy-buffering pathways were also prominently represented, with CKMT1A and GATM increased in ChRCC plasma. KIM-1 (HAVCR1) and leptin were downregulated in ChRCC relative to ccRCC, consistent with the known roles of these proteins in ccRCC biology. Pathway enrichment (KEGG, Reactome) revealed strong overrepresentation of mitochondrial protein degradation (Fold Enrichment 27, q = 3×10-24), fatty acid β-oxidation (Fold Enrichment 31, q = 9×10-11), aerobic respiration and respiratory electron transport (Fold Enrichment 9, q = 3×10-11), suggesting that ChRCC sheds a unique mitochondrial signature into the peripheral circulation. To identify discriminant mitochondrial markers, we applied a bootstrap-based LASSO logistic regression restricted to MitoCarta-annotated proteins upregulated in ChRCC versus ccRCC, with out-of-bag validation across 100 iterations. The model consistently selected ECI1, a key enzyme in β-oxidation, and CKMT1A, a mitochondrial creatine kinase involved in high-energy phosphate transfer. Analysis of TCGA shows that ECI1 and CKMT1A mRNA expression is significantly higher in ChRCC compared to ccRCC. CKMT1A protein levels are elevated in ChRCC relative to normal kidney (log2 fold change = 6.2) in a published proteomics analysis (Xiao et al., Cancer Research, 2020), further highlighting CKMT1A upregulation as part of the broader mitochondrial metabolic program in ChRCC. Together, the LASSO model achieved a mean out-of-bag AUROC of 0.964. Conclusions: The ChRCC plasma proteome is dominated by broad upregulation of mitochondrial metabolic enzymes, revealing a systemic metabolic phenotype strikingly aligned with the known histologic accumulation of abnormal mitochondria in ChRCC cells. Citation Format: Tiegang Han, Clara Steiner, Steven Safi, Wafaa Bzeih, Hadi Mansour, Eddy Saad, Jessica F. Williams, Michelle S. Hirsch, Vinay Giri, Liliana Ascione, Yehonatan Elon, Adam Dicker, Yan Tang, Toni K. Choueiri, Elizabeth P. Henske, Wenxin Xu. A mitochondrial plasma proteomic signature identifies metastatic chromophobe RCC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B024.