title: Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer.
abstract: OBJECTIVE
  To investigate whether prognosis of patients with high-risk gastric cancer may depend on MET copy number gain (CNG) or an activating truncation within a deoxyadenosine tract element (DATE) in the promoter region of the MET ligand HGF.
  
  
  METHODS
  A single-institution cohort of 230 patients with stage II/III gastric cancer was studied. Formalin-fixed paraffin-embedded tumor specimens were used for DNA extraction. Quantitative polymerase chain reaction (qPCR) for MET CNG and sequencing for HGF DATE truncation (< 25 deoxyadenosines instead of 30) were used. Results were analyzed for association with disease-free survival (DFS) and overall survival (OS). To assess the reliability of the qPCR measurement, a random sample of cases was reanalyzed using an alternative assay (fluorescent in situ hybridization [FISH]) with calculation of the intracorrelation coefficient (ICC).
  
  
  RESULTS
  In 216 assessable patients, MET CNG five or more copies and homozygous HGF-truncated DATE occurred in 21 patients (10%) and 30 patients (13%), respectively. Patients with MET CNG five or more copies (MET-positive) showed significantly worse prognosis with multivariate hazard ratio (HR) of 3.02 (95% CI, 1.71 to 5.33; P < .001) for DFS and multivariate HR of 2.91 (95% CI, 1.65 to 5.11; P < .001) for OS. The agreement between qPCR and FISH was high, with ICC = 0.9% (95% CI, 0.81% to 0.95%; the closer the ICC is to 1, the greater is the agreement). HGF-truncated DATE did not show relevant prognostic effect.
  
  
  CONCLUSIONS
  In this study, qPCR revealed approximately 10% of white patients with gastric cancer harboring MET CNG of five or more copies. This marker was significantly associated with unfavorable prognosis. This information is relevant to the current clinical development of anti-MET compounds.
authors: Azienda Ospedaliera Ospedali Riuniti Marche Nord 61122, Pesaro, Italy. frada@tin.it
authors: Francesco
authors: F
authors: Graziano
authors: Nadia
authors: N
authors: Galluccio
authors: Paola
authors: P
authors: Lorenzini
authors: Annamaria
authors: A
authors: Ruzzo
authors: Emanuele
authors: E
authors: Canestrari
authors: Silvia
authors: S
authors: D'Emidio
authors: Vincenzo
authors: V
authors: Catalano
authors: Valerio
authors: V
authors: Sisti
authors: Claudia
authors: C
authors: Ligorio
authors: Francesca
authors: F
authors: Andreoni
authors: Eliana
authors: E
authors: Rulli
authors: Enrico
authors: E
authors: Di Oto
authors: Giammaria
authors: G
authors: Fiorentini
authors: Costantino
authors: C
authors: Zingaretti
authors: Michele
authors: M
authors: De Nictolis
authors: Federico
authors: F
authors: Cappuzzo
authors: Mauro
authors: M
authors: Magnani
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000502:physiology; D012306:Risk; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery
chemical_list: D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met