Circulating mitochondrial proteins as plasma biomarkers for chromophobe renal cell carcinoma.

e16527 Background: Chromophobe renal cell carcinoma (ChRCC) is the second most common subtype of non-clear cell renal cell carcinoma. Arising from the mitochondria-rich intercalated cells of the kidney, ChRCC is characterized by distinct clinical and molecular features. The lack of biomarkers for ChRCC, particularly in metastatic disease, limits diagnostic and therapeutic advancements. This study integrates proteomic and transcriptomic analyses to identify potential biomarkers for ChRCC. Methods: Plasma from a cohort of 199 patients with metastatic ChRCC (n = 7) and clear cell renal cell carcinoma (ccRCC) (n = 192) was analyzed using SomaScan, a high-throughput DNA aptamer-based proteomic assay. Logistic regression analysis was used to identify proteins associated with chromophobe versus clear cell histology. Protein values were log-transformed prior to analysis. Additionally, RNA sequencing (RNA-seq) was performed on 7 ChRCC tumors, comprising matched primary and metastatic tumors from three patients. Differential gene expression analysis was used to evaluate whether proteins elevated in the plasma of ChRCC patients were also overexpressed in tumor tissues. Results: ChRCC plasma samples contained high levels of circulating mitochondrial proteins compared to ccRCC, including succinyl-CoA:3-ketoacid-coenzyme A transferase 1 (SCOT, Odds Ratio [OR] = 5.6, p = 0.0001), ATP synthase subunit O (ATPO, OR = 5.4, p = 0.0005), and cytochrome c oxidase subunit 5A (COX5A, OR = 6.2, p = 0.0007). RNA-seq analysis confirmed high expression of the genes encoding these proteins in both primary and metastatic ChRCC samples, suggesting consistent upregulation throughout disease progression. Conclusions: Circulating mitochondrial proteins are potential minimally invasive biomarkers specific to ChRCC. In line with ChRCC tumor biology, this study identified mitochondrial proteins as potential predictors of chromophobe histology. Analysis of larger cohorts is underway to validate the use of these circulating mitochondrial proteins for the detection and monitoring of ChRCC.