title: Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers.
abstract: OBJECTIVE
  We previously showed that 90% (47 of 52; 95% CI, 0.79 to 0.96) of lung adenocarcinomas from East Asian never-smokers harbored well-known oncogenic mutations in just four genes: EGFR, HER2, ALK, and KRAS. Here, we sought to extend these findings to more samples and identify driver alterations in tumors negative for these mutations.
  
  
  METHODS
  We have collected and analyzed 202 resected lung adenocarcinomas from never smokers seen at Fudan University Shanghai Cancer Center. Since mutations were mutually exclusive in the first 52 examined, we determined the status of EGFR, KRAS, HER2, ALK, and BRAF in stepwise fashion as previously described. Samples negative for mutations in these 5 genes were subsequently examined for known ROS1 fusions by RT-PCR and direct sequencing.
  
  
  RESULTS
  152 tumors (75.3%) harbored EGFR mutations, 12 (6%) had HER2 mutations, 10 (5%) had ALK fusions all involving EML4 as the 5' partner, 4 (2%) had KRAS mutations, and 2 (1%) harbored ROS1 fusions. No BRAF mutation were detected.
  
  
  CONCLUSIONS
  The vast majority (176 of 202; 87.1%, 95% CI: 0.82 to 0.91) of lung adenocarcinomas from never smokers harbor mutant kinases sensitive to available TKIs. Interestingly, patients with EGFR mutant patients tend to be older than those without EGFR mutations (58.3 Vs 54.3, P = 0.016) and patient without any known oncogenic driver tend to be diagnosed at a younger age (52.3 Vs 57.9, P = 0.013). Collectively, these data indicate that the majority of never smokers with lung adenocarcinoma could benefit from treatment with a specific tyrosine kinase inhibitor.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Fang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Han
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Haiquan
authors.initials: H
authors.lastname: Chen
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors