Table 1.

Molecular alterations of MET in human gliomas

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]