Genetic Activation of the MET Pathway and Prognosis of Patients With High-Risk, Radically Resected Gastric Cancer

Abstract

In this study, qPCR revealed approximately 10% of white patients with gastric cancer harboring MET CNG of five or more copies. This marker was significantly associated with unfavorable prognosis. This information is relevant to the current clinical development of anti-MET compounds.

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

“…To accurately detect CNG, we analyzed three different regions of the MET gene: a region spanning exon 3-intron 3 boundaries (TaqMan Copy Number Assay Hs01602615_cn), a region within intron 12 (Hs0527935_cn) and a region spanning intron 20-exon 21 boundaries (Hs02884964_cn). 3 Moreover, previously described probes by Smolen et al 15 were also added for analyses. The region of the probes in MET gene is depicted in Figure 2.…”

“…After amplification, the experiment results containing threshold cycle (Ct) values for the copy number and reference assay was imported into the CopyCaller Software (Applied Biosystems) for post-PCR data analysis as previously described. 3 The copy number gain status and the number of MET copies were assigned on the basis of concordance of result in at least two of the four MET regions of probe.…”

“…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 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. 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.…”