<p>Classification of LUAD and SCLC cell lines based on H3K27ac ChIP-seq data.</p>
Funding
DOD Prostate Cancer Research Program (PCRP)
Dana-Farber/Harvard Cancer Center (DF/HCC)
The Dave Page Cancer Research Fund
American Cancer Society (ACS)
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...LUNGSTRONG Foundation
Pan-Mass Challenge Team 3G
Damon Runyon Cancer Research Foundation (DRCRF)
Fund for Innovation in Cancer Informatics (ICI)
Kure It Cancer Research Foundation
Claudia Adams Barr Program for Innovative Cancer Research
Dana-Farber Cancer Institute Presidential Initiatives Fund
H.L. Snyder Medical Research Foundation
Cutler Family Fund for Prevention and Early Detection
Donahue Family Fund
Congressionally Directed Medical Research Programs (CDMRP)
Prostate Cancer Foundation (PCF)
ARTICLE ABSTRACT
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 EGFR mutant (EGFRm) LUAD.
To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo 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 EGFRm LUAD with or without tSCLC.
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 (n = 24,424), DNA methylation (n = 3,298), and chromatin accessibility (n = 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 EGFRm 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 EGFRm LUAD versus tSCLC with an AUROC of 0.94.
These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma.
