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El Zarif, Talal; Meador, Catherine B.; Qiu, Xintao; Seo, Ji-Heui; Davidsohn, Matthew P.; Savignano, Hunter; Lakshminarayanan, Gitanjali; McClure, Heather M.; Canniff, John; Fortunato, Brad; Li, Rong; Banwait, Mandeep K.; Semaan, Karl; Eid, Marc; Long, Henry; Hung, Yin P.; Mahadevan, Navin R.; Barbie, David A.; Oser, Matthew G.; Piotrowska, Zofia; Choueiri, Toni K.; Baca, Sylvan C.; Hata, Aaron N.; Freedman, Matthew L.;

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

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  • Medientyp: E-Artikel
  • Titel: Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling
  • Beteiligte: El Zarif, Talal; Meador, Catherine B.; Qiu, Xintao; Seo, Ji-Heui; Davidsohn, Matthew P.; Savignano, Hunter; Lakshminarayanan, Gitanjali; McClure, Heather M.; Canniff, John; Fortunato, Brad; Li, Rong; Banwait, Mandeep K.; Semaan, Karl; Eid, Marc; Long, Henry; Hung, Yin P.; Mahadevan, Navin R.; Barbie, David A.; Oser, Matthew G.; Piotrowska, Zofia; Choueiri, Toni K.; Baca, Sylvan C.; Hata, Aaron N.; Freedman, Matthew L.;
  • Erschienen: American Association for Cancer Research (AACR), 2024
  • Erschienen in: Clinical Cancer Research (2024), Seite OF1-OF14
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-24-0466
  • ISSN: 1557-3265; 1078-0432
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: Abstract Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.