JNCI Journal of the National Cancer Institute

JNCI Journal of the National Cancer Institute 2005 97(5):339-346; doi:10.1093/jnci/dji055

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© 2005 Oxford University Press

ARTICLE

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

Affiliations of authors: Hamon Center for Therapeutic Oncology Research (HS, TT, MN, JDM, AFG), Department of Molecular Genetics (JH), Department of Internal Medicine (JDM), Department of Pharmacology (JDM) and Department of Pathology (AFG), University of Texas Southwestern Medical Center, Dallas, TX; Cancer Prevention Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (LL, ZF); Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan (MS, TF); Department of Pathology (IIW) and Department of Thoracic and Cardiovascular Surgery (JAR), University of Texas, MD Anderson Cancer Center, Houston, TX; The Prince Charles Hospital, Brisbane, Australia (KMF); Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan (HL); Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan (HS, ST, NS)

Correspondence to: Adi F. Gazdar, MD, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593 (e-mail: adi.gazdar{at}utsouthwestern.edu).

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.

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Correspondence about this Article

Re: Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers

Jose R. Pardinas, Li Xiao, Jia Zhang, and Kai Li
J Natl Cancer Inst 2006 98: 362-363. [Extract] [Full Text] [PDF]

Editorial about this Article

EGFR Gene Mutations: A Call for Global x Global Views of Cancer

William R. Sellers and Matthew Meyerson
J Natl Cancer Inst 2005 97: 326-328. [Extract] [Full Text] [PDF]

Related Memo to the Media

Press Release: Study Examines Role of EGFR Gene Mutations in Lung Cancer Development

Sarah L. Zielinski
J Natl Cancer Inst 2005 97: 325. [Extract] [Full Text]

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