title: Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor.
abstract: BACKGROUND
  Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma.
  
  
  METHODS
  We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry.
  
  
  RESULTS
  Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy.
  
  
  CONCLUSIONS
  Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Sai F
authors.initials: SF
authors.lastname: Yeung
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Joanna H M
authors.initials: JHM
authors.lastname: Tong
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Peggy P W
authors.initials: PPW
authors.lastname: Law
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Lau Y
authors.initials: LY
authors.lastname: Chung
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Raymond W M
authors.initials: RWM
authors.lastname: Lung
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Carol Y K
authors.initials: CYK
authors.lastname: Tong
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Chit
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Anthony W H
authors.initials: AWH
authors.lastname: Chan
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Innes Y P
authors.initials: IYP
authors.lastname: Wan
authors.affiliation: Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Tony S K
authors.initials: TSK
authors.lastname: Mok
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: kfto@cuhk.edu.hk.
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met