Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

Hisayuki Shigematsu, Li Lin, Takao Takahashi, Masaharu Nomura, Makoto Suzuki, Ignacio I. Wistuba, Kwun M. Fong, Huei Lee, Shinichi Toyooka, Nobuyoshi Shimizu, Takehiko Fujisawa, Ziding Feng, Jack A. Roth, Joachim Herz, John D. Minna, Adi F. Gazdar

研究成果: 雜誌貢獻文章

1797 引文 (Scopus)

摘要

Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. Results: We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P <.001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Conclusions: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers. © Oxford University Press 2005, all rights reserved.
原文英語
頁(從 - 到)339-346
頁數8
期刊Journal of the National Cancer Institute
97
發行號5
DOIs
出版狀態已發佈 - 三月 2 2005
對外發佈Yes

指紋

erbB-1 Genes
Lung Neoplasms
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Mutation
Exons
Non-Small Cell Lung Carcinoma
Missense Mutation
Lung
Neoplasms
Neuroendocrine Tumors
Taiwan
Genes
Histology
Japan
Adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

引用此文

Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., ... Gazdar, A. F. (2005). Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. Journal of the National Cancer Institute, 97(5), 339-346. https://doi.org/10.1093/jnci/dji055

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. / Shigematsu, Hisayuki; Lin, Li; Takahashi, Takao; Nomura, Masaharu; Suzuki, Makoto; Wistuba, Ignacio I.; Fong, Kwun M.; Lee, Huei; Toyooka, Shinichi; Shimizu, Nobuyoshi; Fujisawa, Takehiko; Feng, Ziding; Roth, Jack A.; Herz, Joachim; Minna, John D.; Gazdar, Adi F.

於: Journal of the National Cancer Institute, 卷 97, 編號 5, 02.03.2005, p. 339-346.

研究成果: 雜誌貢獻文章

Shigematsu, H, Lin, L, Takahashi, T, Nomura, M, Suzuki, M, Wistuba, II, Fong, KM, Lee, H, Toyooka, S, Shimizu, N, Fujisawa, T, Feng, Z, Roth, JA, Herz, J, Minna, JD & Gazdar, AF 2005, 'Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers', Journal of the National Cancer Institute, 卷 97, 編號 5, 頁 339-346. https://doi.org/10.1093/jnci/dji055
Shigematsu, Hisayuki ; Lin, Li ; Takahashi, Takao ; Nomura, Masaharu ; Suzuki, Makoto ; Wistuba, Ignacio I. ; Fong, Kwun M. ; Lee, Huei ; Toyooka, Shinichi ; Shimizu, Nobuyoshi ; Fujisawa, Takehiko ; Feng, Ziding ; Roth, Jack A. ; Herz, Joachim ; Minna, John D. ; Gazdar, Adi F. / Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. 於: Journal of the National Cancer Institute. 2005 ; 卷 97, 編號 5. 頁 339-346.
@article{add7c69da84d4377a64c8186c3feb6f1,
title = "Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers",
abstract = "Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. Results: We detected a total of 134 EGFR TK domain mutations in 130 (21{\%}) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51{\%} versus 10{\%}), in adenocarcinomas versus cancer of other histologies (40{\%} versus 3{\%}), in patients of East Asian ethnicity versus other ethnicities (30{\%} versus 8{\%}), and in females versus males (42{\%} versus 14{\%}; all P <.001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8{\%}) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Conclusions: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers. {\circledC} Oxford University Press 2005, all rights reserved.",
author = "Hisayuki Shigematsu and Li Lin and Takao Takahashi and Masaharu Nomura and Makoto Suzuki and Wistuba, {Ignacio I.} and Fong, {Kwun M.} and Huei Lee and Shinichi Toyooka and Nobuyoshi Shimizu and Takehiko Fujisawa and Ziding Feng and Roth, {Jack A.} and Joachim Herz and Minna, {John D.} and Gazdar, {Adi F.}",
year = "2005",
month = "3",
day = "2",
doi = "10.1093/jnci/dji055",
language = "English",
volume = "97",
pages = "339--346",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers

AU - Shigematsu, Hisayuki

AU - Lin, Li

AU - Takahashi, Takao

AU - Nomura, Masaharu

AU - Suzuki, Makoto

AU - Wistuba, Ignacio I.

AU - Fong, Kwun M.

AU - Lee, Huei

AU - Toyooka, Shinichi

AU - Shimizu, Nobuyoshi

AU - Fujisawa, Takehiko

AU - Feng, Ziding

AU - Roth, Jack A.

AU - Herz, Joachim

AU - Minna, John D.

AU - Gazdar, Adi F.

PY - 2005/3/2

Y1 - 2005/3/2

N2 - Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. Results: We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P <.001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Conclusions: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers. © Oxford University Press 2005, all rights reserved.

AB - Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. Results: We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P <.001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Conclusions: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers. © Oxford University Press 2005, all rights reserved.

UR - http://www.scopus.com/inward/record.url?scp=20044364940&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20044364940&partnerID=8YFLogxK

U2 - 10.1093/jnci/dji055

DO - 10.1093/jnci/dji055

M3 - Article

C2 - 15741570

AN - SCOPUS:20044364940

VL - 97

SP - 339

EP - 346

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 5

ER -