title: Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations.
abstract: OBJECTIVE
  We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease.
  
  
  METHODS
  One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets.
  
  
  RESULTS
  No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer.
  
  
  CONCLUSIONS
  Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation.
authors: Laboratories of Molecular Pharmacology, Institute for Cancer Research and Treatment IRCC, Candiolo, Italy.
authors: Francesco
authors: F
authors: Galimi
authors: Davide
authors: D
authors: Torti
authors: Francesco
authors: F
authors: Sassi
authors: Claudio
authors: C
authors: Isella
authors: Davide
authors: D
authors: Corà
authors: Stefania
authors: S
authors: Gastaldi
authors: Dario
authors: D
authors: Ribero
authors: Andrea
authors: A
authors: Muratore
authors: Paolo
authors: P
authors: Massucco
authors: Dimitrios
authors: D
authors: Siatis
authors: Gianluca
authors: G
authors: Paraluppi
authors: Federica
authors: F
authors: Gonella
authors: Francesca
authors: F
authors: Maione
authors: Alberto
authors: A
authors: Pisacane
authors: Ezio
authors: E
authors: David
authors: Bruno
authors: B
authors: Torchio
authors: Mauro
authors: M
authors: Risio
authors: Mauro
authors: M
authors: Salizzoni
authors: Lorenzo
authors: L
authors: Capussotti
authors: Timothy
authors: T
authors: Perera
authors: Enzo
authors: E
authors: Medico
authors: Maria Flavia
authors: MF
authors: Di Renzo
authors: Paolo M
authors: PM
authors: Comoglio
authors: Livio
authors: L
authors: Trusolino
authors: Andrea
authors: A
authors: Bertotti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; C066855:HGF protein, human; C544162:MACC1 protein, human; D047428:Protein Kinase Inhibitors; D017978:Receptors, Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met