A Mitochondrial Plasma Proteomic Signature Identifies Metastatic Chromophobe Renal Cell Carcinoma

Chromophobe renal cell carcinoma (ChRCC) is characterized by the accumulation of abnormal mitochondria, a high rate of mitochondrial DNA (mtDNA) mutations, and altered oxidative metabolism. There are no existing circulating biomarkers to distinguish metastatic ChRCC from clear cell renal cell carcinoma (ccRCC).

High-throughput plasma proteomic profiling using the SomaScan platform was performed in 18 ChRCC (including 16 metastatic ChRCC) and 197 metastatic ccRCC patients. Data were harmonized to generate a unified 7K-protein matrix.

Differential expression analysis was performed using limma (version 3.62.2). Of 7272 quantified human plasma proteins, 209 were differentially expressed between ChRCC and ccRCC. Upregulated proteins in ChRCC included essential β-oxidation enzymes such as ECH1 (enoyl-CoA hydratase 1) and ECI1 (enoyl-CoA delta-isomerase 1), suggesting increased long-chain fatty acid degradation. Creatine and energy-buffering pathways were also represented, with increased CKMT1A (Creatine Kinase, Mitochondrial 1A) in ChRCC. KIM-1 (Kidney Injury Molecule-1) and leptin were lower in ChRCC, consistent with the known upregulation of these proteins in ccRCC. Pathway enrichment analyses revealed an overrepresentation of mitochondrial protein degradation, fatty acid β-oxidation, and respiratory electron transport in ChRCC, suggesting that ChRCC sheds a unique mitochondrial signature into the peripheral circulation. A bootstrap-based LASSO logistic regression restricted to upregulated mitochondrial proteins in ChRCC vs. ccRCC consistently selected ECI1 and CKMT1A. The LASSO model achieved an AUROC of 0.964.

Compared to ccRCC, the plasma proteome of metastatic ChRCC is dominated by mitochondrial metabolic enzymes, revealing a systemic metabolic phenotype strikingly aligned with the known histologic accumulation of abnormal mitochondria in ChRCC cells.