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Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling

ABSTRACT: Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling

PROVIDER: PRJNA1123604 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29662700_1.fastq.gz	Fastqsanger.gz
	SRR29662700_2.fastq.gz	Fastqsanger.gz
	SRR29662701_1.fastq.gz	Fastqsanger.gz
	SRR29662701_2.fastq.gz	Fastqsanger.gz
	SRR29662702_1.fastq.gz	Fastqsanger.gz

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Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling

Project description:Histologic transformation to small cell lung cancer (SCLC) is an increasingly common resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutant lung adenocarcinoma (LUAD) that is underdiagnosed in clinical practice due to the requirement for tissue biopsy. Early and accurate detection of transformed (t)SCLC has important prognostic and therapeutic implications. To address this unmet need, we first comprehensively profiled the epigenomes of metastatic lung tumors finding widespread epigenomic reprogramming during histologic transformation from LUAD to SCLC. We then utilized a novel approach for epigenomic profiling of cell-free DNA, which discriminated patients with EGFR mutant tSCLC from patients with EGFR mutant LUAD with greater than 90% accuracy. This first demonstration of the ability to accurately, and non-invasively, detect small cell transformation in patients with EGFR mutant LUAD through epigenomic cfDNA profiling is a critical step towards a new paradigm of diagnostic and therapeutic precision for patients with advanced lung cancer.

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Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling.

Project description:PurposeHistologic 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.Experimental designTo 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.ResultsAnalysis 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.ConclusionsThese data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma.

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