Subtyping of Small Cell Lung Cancer using plasma cell-free nucleosomes

Small cell lung cancer (SCLC) is an aggressive malignancy with exceptionally poor prognosis and limited therapeutic advances in the past few decades. Although SCLCs are treated as a single disease entity in clinic, emerging data support subtypes of SCLC driven by expression of distinct transcription regulators, which engender unique therapeutic vulnerabilities. However, the translational potential of these observations is limited by access to tumor biopsies. Here, we apply chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 299 plasma samples from patients with advanced SCLC, non-SCLC cancers, and healthy adults. We find that cfChIP-seq reliably estimates SCLC circulating free DNA (cfDNA) tumor fraction, recovers the unique epigenetic states of SCLC tissue and cell of origin, and importantly tumor gene expression. Comparison of cfChIP-seq signals to matched tumor transcriptome shows genome-wide concordance particularly in SCLC lineage-defining transcription factors, presenting a direct link between gene expression in the tumor and plasma cell-free nucleosomes. This work sets the stage to non-invasively profile SCLC transcriptomes using plasma cfDNA histone modifications.