MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome

Abstract

Background:The aim of this study was to compare gene copy number (GCN) and protein expression of MET and to evaluate their prognostic roles in gastric carcinomas.Methods:MET protein expression and gene amplification (GA) status were determined by immunohistochemistry (IHC) and silver in-situ hybridisation (SISH), respectively, in a large series of gastric carcinoma.Results:Protein overexpression was observed in 104 of 438 cases, with IHC 2+ in 94 and IHC 3+ in 10, and high polysomy of chromosome 7 and GA were found in 61 and 13 of 381, respectively. Direct comparison revealed a significant correlation between high level of protein expression and increased GCN. All cases with GA showed protein overexpression. Furthermore, all with IHC 3+ showed GA except 1, even which could be categorised as GA according to the ASCO/CAP guideline for human epidermal growth factor receptor 2 assessment. IHC 3+ and GA were significantly associated with poor prognosis.Conclusion:MET IHC reflects well on GA, and therefore, it could be a primary screening test for patient selection for anti-MET therapy if GA is a major determinant of drug responsiveness. Also, the prognostic role of MET indicates that anti-MET therapy is a very promising modality in adjuvant treatment for gastric cancer.

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

“…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.…”

“…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. 16 The lack of a reliable method for evaluating MET immunohistochemistry has caused discrepancies in previous studies. In our comprehensive study, we first proved that both membranous and cytoplasmic MET staining correlate well with mRNA expression levels, amplification of MET gene and clinical outcome.…”

“…[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. 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.…”

“…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.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…For example, recent IHC studies performed on gastric tumour samples have reported cMET over-expression in 4-63% of cases [72][73][74][75][76][77] and various studies performed in ovarian cancer estimate high expression of cMET to be present in 11-68 % of cases [30,22,23,26,25] (Table 1). The majority of the estimates above come from IHC studies, using a number of different antibodies, but no consensus on scoring criteria yet exists, nor whether cytoplasmic or membranous staining for cMET is important.…”