Table 1 Molecular alterations of MET in human gliomas
From: MET in glioma: signaling pathways and targeted therapies
Alteration | Findings | Population | Technique | Evaluation | Ref. |
|---|---|---|---|---|---|
Overexpression | 31.2% (63/202) of GBMs displayed overexpression of MET. | TCGA data | CGH | Analyzed TCGA Network datasets from 202 patients via in silico assays for the expression of MET. | [32] |
Overexpression | 45% (31/69) of glioblastoma patients displayed positive expression of MET. | Turkey | IHC | Tumors were scored positive if more than 30% of cells expressed c-Met. | [34] |
Overexpression | 79% (15/19) of the patients with recurrent GBM displayed MET overexpression. 37%(7/19) of the patients with primary GBM displayed MET overexpression. | China | IHC | Tumors were scored positive if more than 30% of cells expressed c-Met. | [35] |
Amplifcation | MET gain was detected in primary glioblastomas (16/34, 47%) and secondary glioblastomas (16/36, 44%). MET gain was also common in diffuse astrocytomas (43/112, 38%), but less frequent in oligodendrogliomas (13/82, 16%). | Switzerland, Germany, Japan, France | qPCR | Gain was considered as a copy number > 2.699. | [36] |
Mutation and fusion genes | The frequency of METex14 in secondary GBM is 14% (11/78), in LGG is 1% (6/530) and in primary GBM is 1.7% (3/174). ZM fusions were identified in four secondary GBM cases co-occur with METex14. | China, Korea | Sanger sequencing | Certain primers and DNA polymerase were used to amplify the fragments. The amplification product bands were extracted from agarose gel after electrophoresis and verified by Sanger sequencing with normal sequence. | [20] |
Amplification | MET amplification was detected in four cases in a cohort of 108 GBM. | France | CGH, FISH | For CGH, MET amplification was defined by a log ratio cya5/cya3 > 1.8. For FISH, amplification of MET was defined as more than six copies of MET gene per cell and a ratio MET/CEN7 > 2.2 in more than 10% of cells. | [37] |
Overexpression | MET overexpression (> 10%) was detected in 27 out of 104 nonamplified GBM. | France | IHC | The percentage of positive cells > 10% was considered as MET overexpressed. | [37] |
Amplification | 4% of GBM harbor an amplification of MET gene. | TCGA data | Sanger sequencing | Whole-genome-amplified genomic DNA samples from tumours and normal samples were sequenced by the Sanger method. | [7] |
Mutation | METΔ7–8 mutation (lacks exons 7 and 8) is expressed in 6% (6/102) of grade III and IV gliomas. | Netherland | PCR | Performed the exon 6–9 (MET) PCR on cDNA, and then verified by Sanger sequencing. | [42] |
Fusion genes | ZM fusion was found in 15% (6/40) of secondary glioblastomas. | China | Sanger sequencing | Two algorithms, deFuse (deFuse-0.6.1) (McPherson et al.2011) and TopHat-Fusion (TopHatFusion-0.1.0) (Kim and Salzberg 2011), were used to detect gene fusion based on the paired-end reads in different samples. | [43] |
Fusion genes | Detected two previously unknown fusions of MET:TFG-MET and CLIP2-MET (lack tyrosine 1003 [Y1003], which negatively regulates MET by recruiting ubiquitin ligases), and identified two with a PTPRZ1-MET fusion in 53 pediatric glioblastomas. | German | PCR, DNA sequencing | Paired-end library preparation was conducted using Illumina v2 protocols. Genomic DNA (~ 1 μg) was fragmented to an insert size of ~ 300 bp with a Covaris device, and size selection was performed using agarose gel excision. Deep sequencing was carried out with Illumina HiSeq 2000 instruments. | [44] |
Amplification | 2% of the 206 GBM cases showed MET amplification. | TCGA data | FISH | In cases where minimum of 1000 tumor cells were present, populations with and without amplification were quantified. | [29] |
Mutation | A GGA to GTA mutation, resulting in glycine to valine substitution in codon 1137 of MET was confirmed in one case in all the 11 GBMs. | American | PCR-SSCP | Exons 15, 16, 17, 18, and 19, the most commonly affected regions of the MET gene, was analyzed for MET mutations via SSCP and sequencing. | [105] |
Amplification | One glioma (1/11) showed MET amplification exhibiting 20 to 100 copies of MET signal in each affected cell. | American | FISH | At least 100 interphases with strong hybridization signals were scored. Normal brain tissue control showed,6% of cells with one MET gene signal. Alterations of MET copy numbers were scored when present in at least 30% of cells. | [105] |
Overexpression | 13.1% (18/137) of the GBMs displayed c-Met overexpression. | Korea | IHC | Positivity was measured by Aperio membrane algorithm after scanning with Aperio Scanscope, which appeared as positive %. | [106] |
Amplification | 5.1% (7/137) of the GBMs displayed MET gene amplifcation. | Korea | FISH | The processing and analysis of the FISH studies were conducted. The signals on 100 non-overlapping intact nuclei were counted. | [106] |