title: Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA.
abstract: 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.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Izumchenko
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Mariana
authors.identifier: http://orcid.org/0000-0002-1652-8921
authors.initials: M
authors.lastname: Brait
authors.affiliation: Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Elana
authors.initials: E
authors.lastname: Fertig
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Luciane T
authors.initials: LT
authors.lastname: Kagohara
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Bedi
authors.affiliation: Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Ravi
authors.affiliation: Personal Genome Diagnostics, Inc., 2809 Boston Street, Suite 503, Baltimore, Maryland 21224, USA.
authors.forename: Sian
authors.initials: S
authors.lastname: Jones
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Mohammad O
authors.initials: MO
authors.lastname: Hoque
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Westra
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D065311:Adenocarcinoma in Situ / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells; D004247:DNA / Q000235:genetics*; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)