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The Impact of Sex and Smoking Status on the Mutational Spectrum of Epidermal Growth Factor Receptor Gene in Non–small Cell Lung Cancer

Authors' Affiliations: Departments of ¹ Cancer and Thoracic Surgery and ² Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Divisions of ³ Epidemiology and Prevention, ⁴ Thoracic Surgery, and ⁵ Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan; ⁶ The Prince Charles Hospital, Brisbane, Australia; ⁷ Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan; ⁸ Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁹ Hamon Center for Therapeutic Oncology Research and ¹⁰ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Shinichi Toyooka, Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7265; Fax: 81-86-235-7269; E-mail: toyooka{at}md.okayama-u.ac.jp.

Purpose: Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non–small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation.

Experimental Design: We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum.

Results: Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference.

Conclusion: Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.