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

Evgeny Izumchenko, Xiaofei Chang, Mariana Brait Rodrigues De Oliveira, Elana Fertig, Luciane Tsukamoto Kagohara, Atul Bedi, Luigi Marchionni, Nishant Agrawal, Rajani Ravi, Sian Jones, Mohammad Hoque, William H. Westra, David Sidransky

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number8258
JournalNature Communications
Volume6
DOIs
StatePublished - Sep 16 2015

Fingerprint

neoplasms
sequencing
Ports and harbors
progressions
lungs
Tumors
Lung Neoplasms
deoxyribonucleic acid
DNA
Hyperplasia
Neoplasms
Adenocarcinoma
Alveolar Epithelial Cells
harbors
mutations
markers
Carcinogenesis
tumors
Polymerase Chain Reaction
Lung

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

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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.",
author = "Evgeny Izumchenko and Xiaofei Chang and {Brait Rodrigues De Oliveira}, Mariana and Elana Fertig and {Tsukamoto Kagohara}, Luciane and Atul Bedi and Luigi Marchionni and Nishant Agrawal and Rajani Ravi and Sian Jones and Mohammad Hoque and Westra, {William H.} and David Sidransky",
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language = "English (US)",
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AU - Izumchenko, Evgeny

AU - Chang, Xiaofei

AU - Brait Rodrigues De Oliveira, Mariana

AU - Fertig, Elana

AU - Tsukamoto Kagohara, Luciane

AU - Bedi, Atul

AU - Marchionni, Luigi

AU - Agrawal, Nishant

AU - Ravi, Rajani

AU - Jones, Sian

AU - Hoque, Mohammad

AU - Westra, William H.

AU - Sidransky, David

PY - 2015/9/16

Y1 - 2015/9/16

N2 - 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.

AB - 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.

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