Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy. ### Competing Interest Statement S.R.V. acknowledges Support from the Doris Duke Charitable Foundation (Clinical Scientist Development Award, 2020101), R01CA279044, and the V Foundation (V Scholar Award, V2022-018). S.R.V.: Consulting (current or past 3 years): Jnana Therapeutics. Research support from Bayer. Spouse is an employee of and holds equity in Kojin Therapeutics. D.A.B. reports honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, consulting fees from Merck, Pfizer, and Elephas, equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics, personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Accolade 2nd.MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, and Scholar Rock, and research support from Exelixis and AstraZeneca, outside of the submitted work. S.C.B., T.K.C. and M.L.F. are co-founders and shareholders of Precede Biosciences. SCB is supported by grant W81XWH-21-1-0299 from the Department of Defense, a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation, the Kure It Cancer Research Foundation, and the Fund for Innovation in Cancer Informatics. The remaining authors report no competing interests.