Annotation Detail

Information
Associated Genes
MET
Associated Variants
MET OVEREXPRESSION ( ENST00000318493.11 )
MET OVEREXPRESSION ( ENST00000318493.11 )
Associated Disease
skin melanoma
Source Database
CIViC Evidence
Description
Whole exome sequencing, transcriptome and methylome alterations in 48 melanoma samples with acquired resistance to BRAFi +/- MEKi therapy compared to patient-matched baseline melanoma tissues were analyzed. 39% of resistant melanomas were not accounted for by any validated mutational mechanism. c-MET was overexpressed in 21 of 48 (44%) resistant samples. Methylome analysis revealed three CpG clusters (C1–3) with differential methylation to be negatively correlated with differential c-MET mRNA expression. In nearly all (90%) pairwise comparisons of tumors and cell lines, differential c-MET mRNA expression could be accounted for by at least one differential CpG cluster methylation (Δβ ≥ 10% and FDR adjusted p ≤ 0.05). In contrast, only 48% displayed a concordant differential expression pattern of at least one c-MET transcription factor. In an independent study, c-MET was overexpressed in 8 of 35 (23%) MAPKi-resistant tumors from 7 of 26 (27%) patients. In two human BRAF V600E mutant cell lines, BRAFi treatment led to progressive methylation-expression changes akin to observations across MAPKi-sensitive versus resistant tumors.
Variant Origin
N/A
Variant Origin
N/A
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/1581
Gene URL
https://civic.genome.wustl.edu/links/genes/52
Variant URL
https://civic.genome.wustl.edu/links/variants/621
Rating
4
Evidence Type
Predictive
Disease
Skin Melanoma
Evidence Direction
Supports
Drug
Vemurafenib
Evidence Level
B
Clinical Significance
Resistance
Pubmed
26359985
Drugs
Drug NameSensitivitySupported
VemurafenibResitance or Non-Reponsetrue