title: MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis.
abstract: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non-small cell lung carcinoma (NSCLC).
  
  
  
  Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.
  
  
  
  METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.
  
  
  
  The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048-56. ©2016 AACRSee related commentary by Drilon, p. 2832.
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Joanna H
authors: JH
authors: Tong
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Sai F
authors: SF
authors: Yeung
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Anthony W H
authors: AW
authors: Chan
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Lau Y
authors: LY
authors: Chung
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Shuk L
authors: SL
authors: Chau
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Raymond Wai Ming
authors: RW
authors: Lung
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Carol Y
authors: CY
authors: Tong
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Chit
authors: C
authors: Chow
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Edith K Y
authors: EK
authors: Tin
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Yau H
authors: YH
authors: Yu
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Hui
authors: H
authors: Li
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Yi
authors: Y
authors: Pan
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors: Wing P
authors: WP
authors: Chak
authors: Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
authors: Calvin S H
authors: CS
authors: Ng
authors: Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong.
authors: Tony S K
authors: TS
authors: Mok
authors: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. kfto@cuhk.edu.hk.
authors: Ka F
authors: KF
authors: To
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met