title: Frequency of well-identified oncogenic driver mutations in lung adenocarcinoma of smokers varies with histological subtypes and graduated smoking dose.
abstract: OBJECTIVE
  We performed this analysis to reveal the association between six well-identified oncogenic driver mutations and clinical and pathological features in lung adenocarcinomas from smokers. It may have the potentiality to optimize existing treatment strategies and clinical trial design.
  
  
  METHODS
  In this series, 230 resected lung adenocarcinomas from smoker (>100 cigarettes in lifetime) at single center (Shanghai Cancer Center, Shanghai, China) were tested for mutation in EGFR, KRAS, BRAF, HER2, EML4-ALK and PIK3CA. Further we compared the mutation frequency with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype.
  
  
  RESULTS
  Among 230 smokers, we detected 100 (43.5%) EGFR mutations, 38 (16.5%) KRAS mutations, 8 (3.5%) PIK3CA mutations, 7 (3.0%) BRAF mutations and 7 (3.0%) EML4-ALK fusions. No HER2 mutation was found. EGFR mutations occurred at a significantly higher frequency in patients with smoking dose ≤20 pack-years (p < 0.001) or age ≥60 years old at diagnosis (p = 0.018). Smoking dose >20 pack-years and age <60 years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation frequency, EGFR mutation had positive correlation with histological subtype micropapillary (p = 0.003), lepidic (p = 0.011), as well as papillary (p = 0.05) predominant adenocarcinoma. Negative correlation was found between EGFR mutation and solid predominant (p < 0.001), as well as invasive mucinous adenocarcinoma (IMA) (p = 0.006). Besides, KRAS mutation had positive correlation with IMA (p = 0.043). The frequency of EGFR mutation decreased with increasing tobacco dose. In contrast, higher frequency of KRAS mutations was observed with increasing tobacco dose. Generally, the frequency of these driver mutations tested in our study decreased with increasing smoking dose.
  
  
  CONCLUSIONS
  This study represents the first comprehensive and concurrent analysis of these six well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases.
authors.affiliation: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Pan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Haichuan
authors.initials: H
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Ye
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Yihua
authors.initials: Y
authors.lastname: Sun
authors.forename: Haiquan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D002681:China; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D018631:ras Proteins / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human