cfDNA methylome profiling for detection and subtyping of small cell lung cancers.

Francesca Chemi, Simon Pearce, Alexandra Clipson, Steven Hill, Alicia-Marie Conway, Sophie Alice Richardson, K Kamieniecka, R Caeser, Daniel White, S Mohan, V Foy, Kathryn Simpson, M Galvin, KK Frese, Lynsey Priest, J Egger, Alastair Kerr, PP Massion, John Poirier, Gerard BradyF Blackhall, Dominic Rothwell, Charles Rudin, Caroline Dive

Research output: Contribution to journalArticlepeer-review


Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients' circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.
Original languageEnglish
Pages (from-to)1260-1270
Number of pages11
JournalNature Cancer
Issue number10
Early online date8 Aug 2022
Publication statusPublished - 1 Oct 2022


  • Animals
  • Cell-Free Nucleic Acids/genetics
  • DNA Methylation/genetics
  • Epigenome/genetics
  • Lung Neoplasms/diagnosis
  • Mice
  • Small Cell Lung Carcinoma/diagnosis
  • Transcription Factors/genetics


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