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

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

Author information

1
Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
2
Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
3
Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
4
Personal Genome Diagnostics, Inc., 2809 Boston Street, Suite 503, Baltimore, Maryland 21224, USA.
5
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
6
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

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.

PMID:
26374070
PMCID:
PMC4595648
DOI:
10.1038/ncomms9258
[Indexed for MEDLINE]
Free PMC Article
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