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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.

2024-06-20 | GSE269746 | GEO

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.

| S-EPMC11369616 | biostudies-literature

Methylation analysis of serum cfDNA pooled samples for the discovery of non-invasive biomarkers for colorectal cancer

Project description:We explored the differential methylation patterns found in cfDNA between no neoplasia (NN; individuals with no colorectal findings, benign pathologies and non-advanced adenomas) and patients with advanced neoplasia (AN; advanced adenomas and colorectal cancer) using pooled samples, for the discovery of non-invasive methylation biomarkers for CRC screening. cfDNA was extracted from serum samples and methylation measurements were assessed with the Infinium MethylationEPIC BeadChip. Data was mainly preprocessed and analyzed with R/Bioconductor packages.

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Histologic transformation induced by EGFR tyrosine kinase inhibitors

Project description:Histologic transformation induced by EGFR tyrosine kinase inhibitors

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Histologic transformation induced by EGFR tyrosine kinase inhibitors

Project description:Although tyrosine kinase inhibitors (TKIs) targeting Epidermal Growth Factor Receptor (EGFR) activating mutations have significantly improved outcomes in EGFR-mutant non-small cell lung cancer, resistance inevitably develops. Despite the heterogeneity of resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. We characterized five cases with ARAF amplification resistant to first- or second-generation EGFR-TKIs and screened an additional 48 re-biopsied specimens following resistance to Osimertinib. Among Osimertinib-resistant tumors, we identified four cases with ARAF amplification. Overall, these nine ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, we identified two cases showing histologic transformation from lung adenocarcinoma to small cell lung cancer (SCLC). SCLC can be classified into four subtypes defined by transcriptional signatures driven by specific transcription factors. To estimate the subtypes of these resistant tumors, RNA sequencing analysis was performed in paired samples before and after treatment with EGFR-TKIs.

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2018-01-10 | E-MTAB-5749 | biostudies-arrayexpress

Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma

Project description:The role of brain immune compartments in glioma evolution remains elusive. We profiled immune cells in glioma microenvironment and the matched peripheral blood from 11 patients at a single-cell level. Notably, glioblastoma exhibits specific infiltration of certain blood-originated monocytes expressing EGFR ligands including EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (P = 0.019), while co-occurring with mesenchymal subtype (P = 4.7x10-7) and marking worse prognosis (P = 0.004 and 0.032 in two independent cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveals remarkable association between elevated TAMo and glioma mesenchymal transformation. Further analysis identifies FOSL2 as a master regulator of TAMo. The roles of FOSL2-EREG/AREG-EGFR signaling axis in promoting glioma invasion were verified experimentally. Collectively, we have identified TAMo in tumor microenvironment and revealed its driving role in activating EGFR signaling to shape glioma evolution.

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Exposure of THP1 cells to plasma containing or lacking cfDNA

Project description:We aimed to clarify the cell-free DNA (cfDNA) physiological role. We exposed THP1 cells to plasma from healthy individuals with and without cfDNA and compared their transcriptomes and proteomes.

2020-12-01 | E-MTAB-8574 | biostudies-arrayexpress

Genome-wide DNA methylation analysis in cfDNA from pancreatic cancer patients

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