Recently it has been reported that mutations in the
tyrosine kinase domain of the
epidermal growth factor receptor(EGFR) gene occur in a subset of patients with
lung cancer showing a dramatic response to EGFR
tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung
carcinogenesis, we sequenced exons 18-21 of the
tyrosine kinase domain using total
RNA extracted from unselected 277 patients with
lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around
codons 746-750 in exon 19, 54 were point mutations including 49 at
codon 858 in exon 21 and 4 at
codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001),
adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with
adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In
adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated
tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in
tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary
adenocarcinoma without KRAS mutations, which is not caused by tobacco
carcinogens.