title: Clinical implications of high MET gene dosage in non-small cell lung cancer patients without previous tyrosine kinase inhibitor treatment.
abstract: BACKGROUND
  Recently, two studies revealed that MET amplification was associated with secondary epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients. But it remains uncertain whether MET amplification could be related to primary TKI resistance in NSCLC because of limited data.
  
  
  METHODS
  MET gene dosage of the tumor tissues from 208 NSCLC patients was investigated by real time quantitative polymerase chain reaction and compared with molecular and clinical features, including EGFR mutations, KRAS mutations, EGFR gene copy numbers, and patient survivals. Three copies were used as the cutoff. Among them, 25 patients were also evaluable for EGFR TKI responsiveness.
  
  
  RESULTS
  The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant. Coexisting EGFR mutations were identified, and the incidence (8.54%) was similar to wild type (12.0%). High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) but not correlated with primary TKI resistance. Among the 155 surgically resectable patients (stage I to IIIA), high MET gene dosage was significantly associated with shorter median survival (21.0 months versus 47.1 months; p = 0.042) by univariate analysis.
  
  
  CONCLUSIONS
  High MET gene dosage was not related to primary TKI resistance and the incidence was increased after chemotherapy, suggesting high MET gene dosage may also be related to chemotherapy resistance.
authors: Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Ya-Ting
authors: YT
authors: Chen
authors: John Wen-Cheng
authors: JW
authors: Chang
authors: Hui-Ping
authors: HP
authors: Liu
authors: Tsung-Fu
authors: TF
authors: Yu
authors: Yu-Ting
authors: YT
authors: Chiu
authors: Jia-Juan
authors: JJ
authors: Hsieh
authors: Ying-Tsong
authors: YT
authors: Chen
authors: Yi-Rong
authors: YR
authors: Chen
authors: Hong-Dar Isaac
authors: HD
authors: Wu
authors: Shiu-Feng
authors: SF
authors: Huang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib