Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA

Nat Commun. 2015 Sep 16:6:8258. doi: 10.1038/ncomms9258.


Lungs resected for adenocarcinomas often harbour minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and fully invasive adenocarcinoma. Despite efforts to identify predictive markers of malignant transformation, alterations driving this progression are poorly understood. Here we perform targeted next-generation sequencing on multifocal AAHs and different zones of histologic progression within AISs and MIAs. Multiregion sequencing demonstrated different genetic drivers within the same tumour and reveal that clonal expansion is an early event of tumorigenesis. We find that KRAS, TP53 and EGFR mutations are indicators of malignant transition. Utilizing droplet digital PCR, we find alterations associated with early neoplasms in paired circulating DNA. This study provides insight into the heterogeneity of clonal events in the progression of early lung neoplasia and demonstrates that these events can be detected even before neoplasms have invaded and acquired malignant potential.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma in Situ / genetics
  • Adenocarcinoma in Situ / pathology
  • Adult
  • Aged
  • Cell Transformation, Neoplastic / genetics*
  • Clone Cells
  • DNA / genetics*
  • Disease Progression
  • ErbB Receptors / genetics*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hyperplasia / genetics
  • Hyperplasia / pathology
  • Lung / pathology*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Polymerase Chain Reaction
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Tumor Suppressor Protein p53 / genetics*


  • KRAS protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • DNA
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • BioProject/PRJNA281261