Amplification of the c-<i>met,</i> c-<i>erbB</i>-2 and Epidermal Growth Factor Receptor Gene in Human Gastric Cancers: Correlation to Clinical Features

Abstract

We examined amplification of the c-met, c-erbB-2, and epidermal growth factor receptor (EGFR) gene in the patients with primary gastric cancer, and compared the data with clinical features in order to clarify the relationship between oncogenic abnormality and clinical features. Oncogene amplifications were examined by slot blot hybridization using DNAs extracted from formalin-fixed and paraffin-embedded tissues of primary gastric cancers. Seven of the seventy cancers (10.0%) had c-met gene amplification, nine (12.9%) had c-erbB-2 gene amplification, and six (8.6%) had EGFR gene amplification, respectively. Eighteen cases (25.7%) exhibited one or multiple oncogene amplification, and two cases (2.9%) exhibited simultaneous amplification of the three genes. The cases with c-met gene amplification tend to show invasive character and were related to peritoneal dissemination. The cases with c-erbB-2 gene amplification were related to lymph node metastasis. The cases with EGFR gene amplification had large tumors and were in highly advanced stage. The survival rate in patients with oncogene amplification was significantly lower than that in patients without amplification. Our data indicated that these genes were related to growth and metastasis of gastric cancer. Furthermore, this study about the three genes suggested that the type of activated gene might decide on the type of metastasis and clinical features.

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

“…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. 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.…”

“…[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.…”

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

“…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].…”

“…The prevalence of MET amplification has thus varied in the literature. Studies based on FISH analysis have identified MET amplification in up to approximately 8 % of patients with gastric cancer [42,49,67,84,88,89], whereas an increase in MET copy number has been found in up to approximately 20 % of gastric cancer patients by Southern blot analysis [41,43] or by polymerase chain reaction (PCR)-based assays [90][91][92] (Table 1). As discussed elsewhere [87], whereas Southern blot analysis and PCR-based assays measure a gain in gene copy number regardless of the underlying mechanism, FISH is able to distinguish gene amplification from polysomy.…”