{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:31:56Z","timestamp":1784932316304,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"CDMRP","doi-asserted-by":"crossref","award":["W81XWH-22-1-0951"],"award-info":[{"award-number":["W81XWH-22-1-0951"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"name":"KCCure Chromophobe Kidney Cancer Research Grant"},{"name":"Dana-Farber\/Harvard Cancer Center Kidney SPORE","award":["2P50CA101942-16"],"award-info":[{"award-number":["2P50CA101942-16"]}]},{"name":"Dana-Farber\/Harvard Cancer Center Kidney SPORE","award":["5P30CA006516-56"],"award-info":[{"award-number":["5P30CA006516-56"]}]},{"name":"Kohlberg Chair at Harvard Medical School Fund"},{"name":"Trust Family Fund"},{"name":"Michael Brigham Fund"},{"name":"Pan Mass Challenge Fund"},{"name":"Hinda and Arthur Marcus Fund"},{"name":"Roger and Kathy Marino Fund for Research Acceleration"},{"name":"Frank Shaughnessy Kidney Cancer Research Fund"},{"name":"Loker Pinard Funds"},{"name":"Tuttle Fund for Chromophobe RCC Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: 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). Methods: 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. Results: 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 \u03b2-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 \u03b2-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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/cancers18061032","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T08:47:42Z","timestamp":1774255662000},"page":"1032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Mitochondrial Plasma Proteomic Signature Identifies Metastatic Chromophobe Renal Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8640-1636","authenticated-orcid":false,"given":"Clara","family":"Steiner","sequence":"first","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Department of Urology, University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiegang","family":"Han","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Safi","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafaa","family":"Bzeih","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Mansour","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Saad","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6696-7909","authenticated-orcid":false,"given":"Jessica F.","family":"Williams","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle S.","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-1003","authenticated-orcid":false,"given":"Vinay K.","family":"Giri","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2807-7400","authenticated-orcid":false,"given":"Liliana","family":"Ascione","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Division of Early Drug Development, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy"},{"name":"Department of Oncology and Hematology (DIPO), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehonatan","family":"Elon","sequence":"additional","affiliation":[{"name":"Oncohost, Binyamina-Giv\u2019at Ada 3057324, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P.","family":"Dicker","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Sidney Kimmel College of Medicine, Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-3217","authenticated-orcid":false,"given":"Toni K.","family":"Choueiri","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth P.","family":"Henske","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8450-2037","authenticated-orcid":false,"given":"Wenxin","family":"Xu","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ajur.2021.11.010","article-title":"Chromophobe Renal Cell Carcinoma: Novel Molecular Insights and Clinicopathologic Updates","volume":"9","author":"Alaghehbandan","year":"2022","journal-title":"Asian J. 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