Fig. 1: Epigenomic profiling of plasma identifies clinically actionable cancer phenotypes.

a, Overview of the method. The indicated epigenetic marks are isolated from plasma via immunoprecipitation (IP). DNA fragments from genomic regions bearing these marks are enriched and quantified via high-throughput sequencing, providing a genome-wide assessment of promoter activity, enhancer activity and DNA methylation. b, Epigenomic datasets generated from plasma. post-BMT, post-bone marrow transplant. c, GO term enrichment for genes near REs that correlate with ctDNA content (CREs). The top 1,000 peaks by significance of correlation with ctDNA were combined for each data type (H3K4me3, H3K27ac, panH3ac and MeDIP) and jointly analyzed. d, Plasma signal from H3K4me3 (left) and DNA methylation (right) at gene promoters (y axis) in healthy donor plasma versus gene expression levels in white blood cells (WBCs; x axis). Each dot represents ~10 aggregated genes with similar WBC expression levels. e, Normalized H3K4me3 cfChIP-seq signal of diagnostic marker genes. Each row represents plasma from a patient with the indicated cancer or a healthy volunteer. Signal at each gene is scaled uniformly across plasma samples to allow for comparison. Promoter signal is shown in orange where gene expression is expected in the corresponding cancer type. f, Normalized H3K4me3 cfChIP-seq signal at the DLL3 promoter stratified by cancer type for n = 202 biologically independent samples. Orange indicates cancer types in which the indicated gene is commonly expressed. P value corresponds to Wilcoxon test between cancer types with and without common expression of DLL3. g, Normalized H3K4me3 cfChIP-seq signal at the ERBB2 promoter for n = 30 biologically independent samples. Samples are stratified by HER2 expression per IHC staining of tumor tissue. P value corresponds to Wilcoxon test between HER2⁺ and HER2⁻ cancers. h, IHC staining of HER2 from a brain metastasis from a patient with CRC (AMP-PL-0020-002). Scale bar, 100 μm. For f and g, only plasma samples with estimated ctDNA content >0.05 are included. For box plots, lower, middle and upper hinges indicate 25th, 50th and 75th percentiles; whiskers extend to 1.5× the interquartile ranges. All P values indicate two-sided tests.