title: Diagnostic algorithm for detection of targetable driver mutations in lung adenocarcinomas: Comprehensive analyses of 205 cases with immunohistochemistry, real-time PCR and fluorescence in situ hybridization methods.
abstract: Analysis of the targetable driver mutations is now recommended in all patients with advanced lung adenocarcinoma. Molecular-based methods are usually adopted, however, along with the implementation of highly sensitive and/or mutation-specific antibodies, immunohistochemistry (IHC) has been considered an alternative method for identifying driver mutations in lung adenocarcinomas.
  
  
  
  A total of 205 lung adenocarcinomas were examined for EGFR mutations and ALK and ROS1 rearrangements using real-time PCR, fluorescence in situ hybridization (FISH) and IHC in parallel. The performance of different commercially available IHC antibody clones toward targetable driver mutations was evaluated. The association between these driver mutations and clinicopathological characteristics was also analyzed.
  
  
  
  In 205 cases we studied, 58.5% were found to harbor EGFR mutations, 6.3% ALK rearrangements and 1.0% ROS1 rearrangements. Compared to molecular-based methods, IHC of EGFR mutations showed an excellent specificity but the sensitivity is suboptimal, while IHC of ALK and ROS1 rearrangements demonstrated high sensitivity and specificity. No significant difference regarding the performance of different antibody clones toward these driver mutations was observed, except that clone SP125 showed a higher sensitivity than 43B2 in the detection of p.L858R of EGFR.
  
  
  
  In circumstances such as poor quality of nucleic acids or low content of tumor cells, IHC of EGFR mutation-specific antibodies could be used as an alternative method. Patients negative for EGFR mutations are subjected to further analysis on ALK and ROS1 rearrangements using IHC methods. Herein, we proposed a lung adenocarcinoma testing algorithm for the application of IHC in therapeutic diagnosis.
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan.
authors: Hua-Lin
authors: HL
authors: Kao
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Yi-Chen
authors: YC
authors: Yeh
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Pathology, Taichung Cheng-Ching Hospital, Taichung, Taiwan.
authors: Chin-Hsuan
authors: CH
authors: Lin
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Wei-Fang
authors: WF
authors: Hsu
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Wen-Yu
authors: WY
authors: Hsieh
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: jan99966@gmail.com.
authors: Hsiang-Ling
authors: HL
authors: Ho
authors: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: tychou@vghtpe.gov.tw.
authors: Teh-Ying
authors: TY
authors: Chou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000465:Algorithms; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
keywords: Driver mutations; Immunohistochemistry; Lung adenocarcinoma; Molecular testing