PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

Genetic and expression analysis of MET, MACC1 and HGF in metastatic colorectal cancer: Response to Met inhibition in patient xenografts and pathological correlations

GALIMI, Francesco;TORTI, DAVIDE;SASSI, FRANCESCO;ISELLA, CLAUDIO;CORA', DAVIDE;GASTALDI, Stefania;GONELLA, FEDERICA;MAIONE, FRANCESCA;SALIZZONI, Mauro;MEDICO, Enzo;DI RENZO, Maria Flavia;COMOGLIO, Paolo;TRUSOLINO, Livio;BERTOTTI, Andrea
2011

Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
17
10
3146
3156
http://clincancerres.aacrjournals.org/content/17/10/3146.long
HEPATOCYTE GROWTH-FACTOR; PRIMARY COLON-CANCER; LIVER METASTASES; KINASE INHIBITORS; BREAST-CANCER; AMPLIFICATION; IDENTIFICATION; PROTOONCOGENE; , CHEMOTHERAPY; SENSITIVITY
Francesco Galimi; Davide Torti; Francesco Sassi; Claudio Isella; Davide Corà; Stefania Gastaldi; Dario Ribero; Andrea Muratore; Paolo Massucco; Dimitrios Siatis; Gianluca Paraluppi; Federica Gonella; Francesca Maione; Alberto Pisacane; Ezio David; Bruno Torchio; Mauro Risio; Mauro Salizzoni; Lorenzo Capussotti; Tim Perera; Enzo Medico; M.F. Di Renzo; Paolo M. Comoglio; Livio Trusolino*; Andrea Bertotti* (*Co-Senior Authors)
File in questo prodotto:
File Dimensione Formato  
2011_Genetic and expression analysis of MET, MACC1 and HGF in metastatic colorectal cancer. Response to Met inhibition in patient xenografts and pathologic correlations.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 980.74 kB
Formato Adobe PDF
980.74 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Galimi et al APERTO.pdf

Accesso aperto con embargo fino al 15/05/2012

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.08 MB
Formato Adobe PDF
1.08 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/110677
Citazioni
  • ???jsp.display-item.citation.pmc??? 55
  • Scopus 100
  • ???jsp.display-item.citation.isi??? 101
social impact