Absence of mutations in the kinase domain of the <i>Met</i> gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas

Park, Won Sang; Oh, Ro Ra; Kim, Young Sil; Park, Jik Young; Shin, Min Sun; Lee, Hun Kyoung; Lee, Sug Hyung; Yoo, Nam Jin; Lee, Jung Young

doi:10.1034/j.1600-0463.2000.d01-44.x

Cited by 56 publications

(33 citation statements)

References 16 publications

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“…5,7,11,14,[16][17][18][19][20][21][22][23]33 Although MET expression showed poor prognostic effects on gastric carcinomas, 7,18,20,21,23 most studies were performed 410 years ago 5,7,17,[19][20][21][22] and interpreted either cytoplasmic or membranous positivity only 5,17-21 without considering intensity. In a recent large cohort study with gastric cancers with the same MET monoclonal antibody as ours, interpretation of membranous staining, which was used for HER2, failed to find any clinical significance and not all MET 3 þ cases exhibited amplification of MET gene.…”

Section: Discussionmentioning

confidence: 99%

“…3 One potential target in gastric cancer was identified as MET proto-oncogene (hepatocyte growth factor receptor) in preclinical studies. 1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its activation has been mostly attributed to gene amplification. [6][7][8] Although earlier Japanese reports described MET gene amplification in approximately 20% of gastric cancers by comparative genomic in situ hybridization or southern blot analysis, [9][10][11][12][13] recent FISH analyses showed rare or no amplification in locally advanced gastric carcinomas.…”

mentioning

confidence: 99%

“…3,14 MET activation through copy number gain measured by quantitative real-time PCR, 3,7,8,14,15 FISH 6,14 or silver in situ hybridization, 16 and protein overexpression assessed by immunohistochemistry have been reported in gastric carcinomas. 5,7,[17][18][19][20][21][22][23] However, there is a wide discrepancy in the incidences and prognostic significances of MET activation in gastric cancer, 3,5,7,8,[14][15][16][17][18][19][20][21][22][23][24] and correlations between copy number gain and protein overexpression have been very poor. 7,14,24 The establishment of selection criteria in identifying sub-populations that may benefit from treatment is a key aspect of further development of anti-MET monoclonal antibody (METMab) and hepatocyte growth factor/scatter factor monoclonal antibody treatment.…”

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confidence: 99%

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MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

et al. 2013

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The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r ¼ 0.465, Po0.0001), increased copy number gain (r ¼ 0.393, P ¼ 0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; Po0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P ¼ 0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r ¼ 0.274, P ¼ 0.002), copy number gain or survival (P40.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors. Recently, the addition of trastuzumab to standard cytotoxic chemotherapy demonstrated significant survival benefit in HER2-positive gastric carcinomas. 2 Nevertheless, HER2 is positive in only a small portion of gastric cancer patients (7-20%); thus, more precise molecular segmentation is urgently needed. 3 One potential target in gastric cancer was identified as MET proto-oncogene (hepatocyte growth factor receptor) in preclinical studies. 1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

et al. 2013

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“…In gastric cancer, gain-of-function mutations of MET are exceedingly rare [38][39][40], with ligand-independent activation of MET having been attributed to gene amplification [41][42][43].…”

Section: Oncogenic Met Activation In Cancermentioning

confidence: 99%

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

Kawakami

Okamoto

2015

Gastric Cancer

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The MET protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to MET amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF-MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with MET amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of MET amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF-MET axis or on MET amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors.

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“…In normal physiology and fetal development, HGF functions in a paracrine fashion. In human cancer, a variety of abnormal mechanisms of c-Met activation have been described, including autocrine stimulation [astrocytoma and select gastric cell lines (9,10)] and ligand-independent activation related to gene rearrangement or mutation (2, 5, 8, 11 -17). However, the majority of human solid tumors seem to have receptor overexpression, without mutation, and are ligand dependent (8).…”

Section: Introductionmentioning

confidence: 99%

Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met–expressing tumors

Francone

Landmann

Chen

et al. 2007

Molecular Cancer Therapeutics

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Abstractc-Met, a receptor tyrosine kinase responsible for cellular migration, invasion, and proliferation, is overexpressed in human cancers. Although ligand-independent c-Met activation has been described, the majority of tumors are ligand dependent and rely on binding of hepatocyte growth factor (HGF) for receptor activation. Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met. The goal of this study was to develop a xenograft model in which human HGF (hHGF) is produced in a controllable fashion in the mouse. Severe combined immunodeficient mice were treated with ade-

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Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas

Cited by 56 publications

References 16 publications

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met–expressing tumors

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