Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations

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. Clin Cancer Res; 17(10); 3146-56. Ó2011 AACR.

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

“…64 However, the data reported on MET gene copy number are in disagreement with previous studies showing that MET amplification is a rare event in primary colorectal cancer tumors. 65,66 This discrepancy may be due to methodological differences as we used a quantitative RT-PCR assay instead of FISH and thus the reported increase in MET gene copy number could be due to a polysomy of chromosome 7 and not locus specific amplification of MET. Moreover, the choice of TOP3A as a reference gene in our experiments, which resides on chromosome 17 whose loss has been associated with transition to carcinoma, may be another reason for this discrepancy; however this possibility was investigated using KRAS as a reference gene and similar results were obtained (unpublished results).…”

Aberrant Expression of Pim-3 Promotes Proliferation and Migration of Ovarian Cancer Cells

“…Metastasis-associated in colon cancer-1 (MACC1) has been reported to promote tumor proliferation and invasion mediated via hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-Met) signaling in colorectal cancer (Stein et al, 2009;Galimi et al, 2011;Migliore et al, 2012). Recently, a clinical study showed that aberrant overexpression of MACC1 may indicate poor prognosis of ovarian cancer patients for early recurrence and distance metastasis (Zhang et al, 2014).…”

Investigation of MACC1-AS1 gene mutations in colorectal cancer

“…MACC1 kolorektal karsinomada tanı koydurucu bir belirteçtir (11). Ayrıca bazı çalışmalar mide (12), akciğer kanseri (13,14), hepatosellüler karsinoma (15), yumurtalık kanseri (17) ve pankreatik kanser (18) metastazında yüksek düzeyde MACC1 mRNA varlığını göstermiştir.…”

“…Çünkü MACC1, birincil kolon kanserine göre yayılımcı kolon kanserinde aşırı ifade olur (5,6,(8)(9)(10). Benzer şekilde, normal dokulara göre birincil kolon kanserinde de aşırı ifade olur (9,11). Bu da, MACC1 mRNA aşırı ifadesinin mide (12), akciğer (13,14), hepatosellüler (15,16), yumurtalık (17) ve pankreatik kanser (18) gibi diğer katı tümörler için sağkalımı ve kanser ilerleyişi için bir biyobelirteç olarak görülebileceğini düşündürmektedir.…”