Cell-free DNA epigenomic profiling enables noninvasive detection and monitoring of translocation renal cell carcinoma
Year: 2026
Type: article
Abstract: gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC, since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC, because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using chromatin immunoprecipitation and sequencing, we distinguished tRCC from clear cell RCC (AUC=0.87) and healthy controls (AUC=0.91) at low tumor fractions (<1%). This work establishes a framework for non-invasive epigenomic detection, diagnosis and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers. SIGNIFICANCE: Translocation renal cell carcinoma (tRCC) is an aggressive fusion-driven subtype of kidney cancer that is frequently misdiagnosed due to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays targeting DNA alterations are suboptimal for use in tRCC due to its paucity of genomic changes. We demonstrate the utility of cell-free chromatin profiling to noninvasively detect and monitor tRCC with high accuracy, a method that could have applicability to other genomically quiet cancers.
DOI: 10.1172/jci195725
Authors: Simon Garinet, Karl Semaan, Jiao Li, Ananthan Sadagopan, John Canniff, Noa Phillips, Kelly Klega, Medha Panday, Hunter Savignano, Matthew P. Davidsohn, Kevin Lyons, Alessandro Medda, Prateek Khanna, Mingkee Achom, Prathyusha Konda, Brad J. Fortunato, Rashad Nawfal, Razane El Hajj Chehade, Ze Zhang, Jillian O’Toole, Jack Horst, Dory Freeman, Rachel Trowbridge, Cindy H. Chau, William D. Figg, Jacob E Berchuck, Brian D. Crompton, Ji-Heui Seo, Toni K. Choueiri, Matthew L. Freedman, Sylvan C. Baca, Srinivas R. Viswanathan
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, Doris Duke Charitable Foundation, V Foundation for Cancer Research, National Foundation for Cancer Research, Rally Foundation, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Movember Foundation, Philippe Foundation, Ligue Contre le Cancer, Servier, Institut Servier, National Institutes of Health, National Cancer Institute
Awards: G107066813, G1596961289, FUNCTIONALLY CHARACTERIZING THE NONCODING GENOME OF METASTATIC PROSTATE CANCER TO IDENTIFY THERAPEUTIC VULNERABILITIES., G2152013059, TUMOR-INTRINSIC AND TUMOR-EXTRINSIC DETERMINANTS OF IMMUNE RESPONSIVENESS IN MIT/TFE TRANSLOCATION RENAL CELL CARCINOMA, G29403152, HARNESSING EPIGENOMICS TO DETECT AND TARGET SARCOMATOID DIFFERENTIATION IN RENAL CELL CARCINOMA., G379534949, G4119534169, G4136751113, G5068590995, G5072629465, G538698522, G5850682332, G594073507, G633455238, G6461959565, UTILIZING CELL-FREE METHYLOMES TO INFORM CLINICAL SCENARIOS IN RENAL CELL CARCINOMA., G792176338, G9000012005, G9000047808, G9000084010, Characterizing genetic risk of cancer across diverse populations through multi-ancestry epigenome profiling and chromatin QTL discovery, Physician Scientist Training in Cancer Research, Molecular mechanisms and therapeutic targeting of activated NRF2 signaling in MiT/TFE translocation renal cell carcinoma
OpenAlex ID: W7127045013