title: High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) mutation has been known to be associated with adenocarcinoma with bronchioloalveolar carcinoma (BAC; lepidic) feature. This study was aimed to characterize the frequency of EGFR mutations and their association with histologic subtypes in Korean nonsmall cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Three hundred eighty-two (88 biopsies and 294 resections) NSCLC patients were investigated for EGFR mutations (exons 18-21) by polymerase chain reaction and direct sequencing method. For the resected adenocarcinoma specimens, histologic subtypes were classified according to both 2004 World Health Organization classification and 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The results were correlated with EGFR mutation and clinicopathologic features.
  
  
  RESULTS
  EGFR mutations were detected in 196 of 382 NSCLCs (51.3%) and were more frequent in women than in men (65.7% versus 34.3%, p < 0.001) and in nonsmokers than in smokers (63.4% versus 32.0%, p < 0.001). Regarding histologic subtypes of adenocarcinoma, mixed acinar and BAC pattern showed the most frequent EGFR mutation (67.6%), followed by mixed papillary and acinar (65.2%), mixed solid and acinar (38.2%), micropapillary and acinar (30.4%), and acinar and mucinous BAC (13.3%). In addition, EGFR mutations were more frequently observed in tumors with BAC or papillary components than those with mucinous BAC or solid components. Identical EGFR mutations were detected in a single tumor showing mixed histological features. EGFR protein expression was seen more frequently in tumors with EGFR mutations than those without EGFR mutations (75.3% versus 24.7%, p=0.003). EGFR mutations were significantly more common in tumors with thyroid transcription factor-1 (TTF-1) expression than those without TTF-1 (p < 0.001), and almost all (92.7%) mutated adenocarcinomas were TTF-1 positive.
  
  
  CONCLUSIONS
  The incidence of EGFR mutations is variable according to histologic subtypes, gender, and smoking history. The mixed acinar and BAC and papillary and acinar subtypes, the presence of BAC (lepidic) or papillary components, EGFR, and TTF-1 protein expression can predict higher EGFR mutation in lung adenocarcinoma. However, intratumoral heterogeneity of EGFR mutation was not found. In addition, relatively high incidence of EGFR mutations in Korean men who smoked with adenocarcinoma histology suggests that these patients should not be left behind EGFR mutation test.
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
authors.forename: Ping-Li
authors.initials: PL
authors.lastname: Sun
authors.forename: Hyesil
authors.initials: H
authors.lastname: Seol
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seol Bong
authors.initials: SB
authors.lastname: Yoo
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.forename: Xianhua
authors.initials: X
authors.lastname: Xu
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Jheon
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Lee
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015994:Incidence; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012907:Smoking / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors