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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Shigematsu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nomura
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Kwun M
authors.initials: KM
authors.lastname: Fong
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Takehiko
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001315:Australia; D018278:Carcinoma, Neuroendocrine / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D020440:Gene Duplication; D018773:Genes, erbB-1 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013624:Taiwan; D014481:United States; D044465:White People / Q000235:genetics*
chemical_list: D004279:DNA, Viral; D011505:Protein-Tyrosine Kinases