title: EGFR mutations in patients with lung adenocarcinoma in southwest China: are G719S/A and L861Q more likely detected in tumors derived from smokers?
abstract: BACKGROUND
  The clinical characteristics of epidermal growth factor receptor (EGFR) hotspot mutations, such as deletions in exon 19, substitution of L858R in exon 21, and mutations in exon 20, have been widely reported in nonsmall cell lung cancer. However, the clinical features of other low frequency EGFR mutations in these four exons (especially the relationship with smoking history), eg, substitutions of G719S/A/C in exon 18 and L861Q in exon 21, remain unclear. This study investigated the relationship between G719S/A/C and L861Q mutations (in exon 18 and 21) and smoking history.
  
  
  METHODS
  Specimens from 194 patients with lung adenocarcinoma were analyzed for EGFR mutations in exons 18-21 by high-resolution melting curve analysis and amplification refractory mutation technology to establish the relationship between G719S/A/C and L861Q mutations and smoking history.
  
  
  RESULTS
  Ninety-six of 194 tumors (49.5%) were confirmed to be EGFR mutation-positive. Among these mutations, 71 of 104 (68.3%) were from never smokers, six of 17 (35.3%) were from former smokers, and 19 of 73 (26.0%) were from current smokers (P< 0.001). The mutation rate in heavy smokers (5/23, 21.7%) was significantly lower than in light smokers (20/67, 29.9%) and never smokers (71/104, 68.3%,P< 0.001). Seven low frequency EGFR mutations (four substitutions of G719S, and G719 A, respectively, and three of L861Q in exon 21) were identified. Five of these mutations were derived from smokers (one former light smoker, one current heavy smoker, and three current light smokers). Four of these patients had been treated with tyrosine kinase inhibitors and all had a partial response, with median overall survival (14.5 months) and median progression-free survival (6.8 months), being longer than in patients with similarly staged lung adenocarcinoma without EGFR mutation or treatment with tyrosine kinase inhibitors (6.8 and 3.1 months, respectively, according to data from an as yet unpublished study at our institution).
  
  
  CONCLUSIONS
  This study provides further evidence that smoking status, include years of smoking and number of cigarettes smoked per day, plays an important role in EGFR mutation in patients with lung adenocarcinoma. Five of seven specimens with G719S/A or L861Q mutations coming from smokers indicates that there may be a relationship between G719S/A or L861Q mutation and smoking history. However, regardless of the influence of smoking, the effectiveness of tyrosine kinase inhibitors was satisfactory in four patients harboring G719S/A and L861Q EGFR mutation.
authors.affiliation: Department of Pathology.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Mou
authors.affiliation: Department of Pathology.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Respiration, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology.
authors.forename: Zengpeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology.
authors.forename: Qingya
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Pathology.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pathology.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathology.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Xiao
keywords: EGFR; G719S/A; L861Q; lung adenocarcinoma; smoking history