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. and Gazdar, Adi, 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. doi:10.1093/jnci/dji055

Author 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.
Title Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers
Journal name Journal of the National Cancer Institute   Check publisher's open access policy
ISSN 0027-8874
Publication date 2005-03
Sub-type Article (original research)
DOI 10.1093/jnci/dji055
Volume 97
Issue 5
Start page 339
End page 346
Total pages 8
Place of publication Oxford, U.K.
Publisher Oxford University Press
Language eng
Subject 110203 Respiratory Diseases
Formatted 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.

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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 1257 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 1472 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 12 Mar 2009, 12:54:21 EST by Ms Julie Schofield on behalf of School of Medicine