Chehade, R. E. H. | Search bioRxiv

bioRxiv2026

Integrated inference of cancer gene expression from cell-free plasma chromatin

Gene expression is a defining determinant of tumor identity, behavior, and therapeutic response, yet remains challenging to measure noninvasively. Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on [~]270,000 gene-sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on >15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred NECTIN4 expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.

genomics↗

bioRxiv2025

Detection and monitoring of translocation renal cell carcinoma via plasma cell-free epigenomic profiling

TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 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. SIGNIFICANCETranslocation 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.

genomics↗