The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.
Toyooka
Shinichi
S
Department of Cancer and Thoracic Surgery, Okayama University, Okayama, Japan. toyooka@md.okayama-u.ac.jp
Matsuo
Keitaro
K
Shigematsu
Hisayuki
H
Kosaka
Takayuki
T
Tokumo
Masaki
M
Yatabe
Yasushi
Y
Ichihara
Syuji
S
Inukai
Michio
M
Suehisa
Hiroshi
H
Soh
Junichi
J
Kiura
Katsuyuki
K
Fong
Kwun M
KM
Lee
Huei
H
Wistuba
Ignacio I
II
Gazdar
Adi F
AF
Mitsudomi
Tetsuya
T
Date
Hiroshi
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology*; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012737:Sex Factors; D012907:Smoking
D066246:ErbB Receptors