43 DSG2 and NPNT are Elevated in the Plasma of Metastatic Chromophobe RCC and are Associated with Poorer Overall Survival

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Abstract Background Chromophobe renal cell carcinoma (ChRCC) is traditionally defined by its unique metabolic reprogramming, including an increase in mitochondrial mass. The mitochondrial plasma proteome of metastatic ChRCC has been recently reported (Steiner et al. Cancers 2026), and we defined a two-protein signature (ECI1 and KCRU) that can accurately distinguish metastatic ChRCC from metastatic clear cell RCC (ccRCC). Here, we focused on the non-mitochondrial plasma proteomic signatures of ChRCC vs. ccRCC. Methods We used the SomaScan aptamer-based platform to identify differentially expressed proteins in patients with metastatic ChRCC (n = 18) compared to ccRCC (n = 197). We then performed cross-validation with tumor transcriptomics data from The Cancer Genome Atlas (TCGA), tissue-based tumor proteomics (Xiao et al., Cancer Research, 2020), and single-cell RNA sequencing (Labaki C, J Clin Oncol, 2025). Results In total, 206 plasma proteins were significantly upregulated in metastatic ChRCC vs. ccRCC, including the 90 mitochondrial proteins previously reported. Six non-mitochondrial proteins, Pregnancy Specific Beta-1-Glycoprotein 9 (PSG9), Kallikrein Related Peptidase 15 (KLK15), Prolactin Induced Protein (PIP), Desmoglein 2 (DSG2), Nephronectin (NPNT), and Legumain (LGMN), showed high-confidence, consistent upregulation across both plasma proteomics and tumor transcriptomics platforms. Specifically, PSG9 (Log2FC: 1.63 SomaScan, 1.38 TCGA) and PIP (Log2FC: 1.42 SomaScan, 4.03 TCGA) are involved in immune regulation and host defense modulation, suggesting a role in immune evasion. KLK15 (Log2FC: 1.52 SomaScan, 4.72 TCGA) and LGMN (Log2FC: 1.08 SomaScan, 1.16 TCGA), which are both proteases, demonstrated significant elevation, which could contribute to extracellular matrix (ECM) degradation and tumor microenvironment remodeling. Two adhesion-related proteins DSG2 (Log2FC: 1.26 SomaScan, 1.64 TCGA) and NPNT (Log2FC: 1.10 SomaScan, 1.63 TCGA) were identified in both SomaScan and TCGA and are also highly expressed in tumor cells compared to normal ICs in scRNA-seq data. DSG2 is increased in the tissue-based proteomics in ChRCC compared to normal kidney tissue (p < 0.0001). DSG2 (Desmoglein 2) is linked to epithelial-mesenchymal transition (EMT) and sarcomatoid transition, while NPNT (Nephronectin) is an integrin ligand involved in metastatic niche formation and cell-matrix adhesion. Survival analysis revealed that high expression of both DSG2 and NPNT is significantly associated with poorer overall survival in ChRCC patients, underscoring their potential as prognostic biomarkers. Conclusions We identified upregulation of PSG9, KLK15, PIP, DSG2, NPNT, and LGMN in the plasma of metastatic ChRCC. The genes encoding these proteins are upregulated in the ChRCC TCGA. DSG2 and NPNT are of particular interest since they are mediators of tumor integrity and metastatic seeding, and high expression of DSG2 and NPNT is associated with poorer overall survival of ChRCC patients in the TCGA. DOD CDMRP Funding yes

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