1206O Clinical subtyping of cancer from blood based on comprehensive epigenomic profiling

Circulating tumor DNA assays that focus on somatic mutation detection in patient plasma are increasingly being incorporated into cancer detection, monitoring and therapy selection. A major limitation of these assays is the inability to assess changes in gene regulation or expression that underlie clinically relevant characteristics of cancer. We developed a novel assay to profile tumor-derived gene regulatory programs from patients’ plasma. Our approach measured histone modifications associated with active gene promoters (H3K4me3) and enhancers (H3K27ac), as well as DNA methylation, from 1cc of plasma. We measured 1,085 genome-wide profiles of gene regulation across 435 samples from 377 individuals. We demonstrated clinical validity by distinguishing cancer phenotypes based on their gene regulatory profiles. Epigenomic profiling of plasma enabled numerous advances by providing robust, clinically actionable proxies for gene expression from blood. We inferred expression of diagnostic markers and drug target genes by exploiting the correlation of plasma signal at gene promoters (Spearman rho=0.90). Plasma-based measurements of enhancer activity at binding sites of transcription factors (TFs) provided a functional activity readout for targetable TFs such as the androgen receptor (AR) in prostate cancer (Pca) and the estrogen receptor (ER) in breast cancer. We additionally detected epigenetic mechanisms of resistance, including activation of the AR gene enhancer in Pca, neuroendocrine trans-differentiation of Pca, and small cell transformation of EGFR-mutant lung adenocarcinoma. We present the largest epigenomic cell-free DNA dataset reported to date. Measuring tumor gene regulatory programs from plasma enables substantial advances in precision oncology by providing clinically actionable insights that are currently only accessible from tumor tissue.