Data from Detecting Small Cell Transformation in Patients with Advanced <i>EGFR</i> Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling

Abstract

<div>AbstractPurpose:<p>Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with <i>EGFR</i> mutant (<i>EGFR</i>m) LUAD.</p>Experimental Design:<p>To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and <i>de novo</i> SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 mL aliquots of plasma from patients with <i>EGFR</i>m LUAD with or without tSCLC.</p>Results:<p>Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (<i>n</i> = 24,424), DNA methylation (<i>n</i> = 3,298), and chromatin accessibility (<i>n</i> = 16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate noninvasive discrimination between patients with <i>EGFR</i>m LUAD versus tSCLC [area under the receiver operating characteristic curve (AUROC) = 0.82–0.87]. A multianalyte cfDNA-based classifier integrating these three epigenomic features discriminated between <i>EGFR</i>m LUAD versus tSCLC with an AUROC of 0.94.</p>Conclusions:<p>These data demonstrate the feasibility of detecting small cell transformation in patients with <i>EGFR</i>m LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma.</p></div>