Activating somatic mutations in the tyrosine kinase domain of MET are found in about 10-15% of sporadic papillary renal cell carcinoma (pRCC). MET mutations are predominantly associated with Type 1 pRCC tumors. The responses to foretanib an oral inhibitor of MET and other tyrosine kinases including VEGFR2, have been described in patients with papillary renal cell cancer.

Nonsynonymous mutations in the MET gene have been described in non-small cell lung cancer (NSCLC) and (small cell lung cancer) SCLC. Increased expression of MET protein was associated with improved progression free survival and overall survival in patients who received MetMAb (an anti-MET antibody) and erlotinib. The activity of MET inhibitors in NSCLC or SCLC tumors with non-kinase domain MET mutations is not yet known.

The MET p. E168D mutation has been reported in various tumors including lung cancer according to the COSMIC database. Some studies indicate that this mutation may be associated with higher affinity for ligand, HGF. In vitro studies in cell lines with cells expressing MET p.E168D may show increased sensitivity to MET inhibitor. According to ClinVar, this particular variant is a likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41627/). The clinical significance of this variant remains to be fully elucidated.

The MET p.T1010I variant has been reported in some tumor types and also has been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. The utility of MET pathway inhibitors also continues to be explored.

A subset of sporadic papillary renal carcinomas were caused by activating mutations in the tyrosine kinase domain of the MET proto-oncogene. Several of the MET mutations (M1268T, D1246 and V11101) were located in codons homologous to codons mutated in other protein receptor tyrosine kinases (Ret M918T, Kit D816V, and c-erbB V1571)

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET E168D has been previously reported in papillary thyroid carcinoma. This mutation is located in the SEMA domain containing the ligand binding site. In vitro study has shown that E168D alters MET functionality in lung cancer. The prognostic and predictive significance of MET mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. Of note, this variant is reported as a likely benign germline variant in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41627/).

The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been shown to increase growth factor independent proliferation and motility in vitro in tumor cell lines in some studies. This mutation has seen more frequently in thyroid carcinomas than in the goiter controls. But its significance has been challenged by other studies which report a low incidence of T1010I mutation in both tumors and controls and not resulting in an enhanced c-MET phosphorylation. The utility of MET pathway inhibitors also continues to be explored. This variant has also been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. Due to conflicting reports of pathogenicity, this variant best characterized as a variant of uncertain significance (VUS) (https://www.ncbi.nlm.nih.gov/clinvar/variation/41624/).

MET is frequently overexpressed in glioblastomas (GBM), and some gliomas show hepatocyte growth factor (HGF) autocrine activation of the MET signaling pathway. Several studies have found that HGF and MET are expressed at higher levels in human gliomas than in control brain tissue, and that expression levels correlate with tumor grade. Some studies have shown that the HGF expression in high-grade (WHO Grade III-IV) tumors was significantly higher than in low-grade (WHO I-II) tumors. Similarly, coexpression of HGF and MET is observed more frequently in Grade IV GBM than in low-grade glioma, consistent with the contribution of an HGF/MET autocrine loop to malignant progression in these tumors. However, MET sequence alterations have been rare. The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been reported in some tumor types and also has been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. The utility of MET pathway inhibitors also continues to be explored.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in 1% of primary prostate cancers and up to 4.4% of metastatic prostate cancers. Studies have suggested that overexpression of c-MET and aberrant activation of the HGF/c-MET axis in prostate cancer is a relatively late event in tumor progression seen in advanced stages of the disease. MET E168D mutation is located in the SEMA domain containing the ligand binding site. The prognostic and predictive significance of MET mutations in prostate cancer is not clear and correlation with other clinical and laboratory findings is necessary.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. Mutations in MET have been reported in 4-9% of cutaneous melanoma. MET E168D has not been reported in melanomas. This mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The prognostic and predictive significance of MET mutations in melanoma is not clear and correlation with other clinical and laboratory findings is necessary.

Activating somatic mutations in the tyrosine kinase domain of MET are found in about 10–15% of sporadic papillary renal cell carcinoma (pRCC). MET mutations are predominantly associated with Type 1 pRCC tumors. The responses to foretanib an oral inhibitor of MET and other tyrosine kinases including VEGFR2, have been described in patients with papillary renal cell cancer.

Amplification of MET, the hepatocyte growth factor receptor, is identified in 7% of Esophagus-Stomach cancer in recent TCGA study. Several studies investigated the relationship between MET amplification and expression with the clinical outcome in patients with gastric cancer, but yielded conflicting results. Multiple clinical trials of using anti-MET agent in the treatment of Esophagus-Stomach cancer are available.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in ~2% of colon cancers. MET E168D mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The prognostic and predictive significance of MET mutations in colon cancer is not clear and correlation with other clinical and laboratory findings is necessary.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in up to 3.3% of low-grade gliomas and 2.2% of glioblastomas. MET E168D mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The predictive and prognostic significance of MET mutations in brain tumors is unclear and needs to be further studied. Correlation with other clinical and laboratory findings is recommended.

This gene is a known cancer gene.

This gene is a known cancer gene.

MET is frequently overexpressed in glioblastomas (GBM), and some gliomas show hepatocyte growth factor (HGF) autocrine activation of the MET signaling pathway. Several studies have found that HGF and MET are expressed at higher levels in human gliomas than in control brain tissue, and that expression levels correlate with tumor grade. Some studies have shown that the HGF expression in high-grade (WHO Grade III--IV) tumors was significantly higher than in low-grade (WHO I--II) tumors. Similarly, coexpression of HGF and MET is observed more frequently in Grade IV GBM than in low-grade glioma, consistent with the contribution of an HGF/MET autocrine loop to malignant progression in these tumors. However, MET sequence alterations have been rare. The MET M362T variant is classified as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/93565/). These results should be interpreted in the clinical context.

Crizotinib

MET amplification may be associated with sensitivity to MET inhibitors. MET amplification is associated with resistance to EGFR inhibitors in EGFR mutated lung cancer. MET alterations are commonly associated with papillary renal-cell carcinoma and it is very rare in clear cell renal cell carcinoma.

The Mesenchymal Epithelial Transition (MET) proto-oncogene encodes the MET receptor tyrosine kinase, also called c-MET or hepatocyte growth factor (HGF) receptor. MET is a ubiquitously expressed cell surface receptor that leads to the activation of several downstream intracellular pathways which promote cellular growth and proliferation, motility, migration and angiogenesis. Dysregulation of MET via gene amplification, germline or somatic mutations or receptor overexpression has been observed in a variety of epithelial cancers, including breast prostate cancer, non-small cell lung cancer, renal papillary carcinoma, hepatocellular and gastric carcinomas. Genetic alterations in MET have been identified in 0.4% of thyroid carcinomas. The prognostic and predictive significance of MET mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. M362T has been identified in the scientific literature, but has not been biochemically characterized and therefore, its effect on protein function is unknown. This variant is reported as a benign/likely benign germline variant in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/93565).

The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been shown to increase growth factor independent proliferation and motility in vitro in tumor cell lines in some studies. Approximately 2% of adenocarcinomas of the stomach harbor MET mutations. The utility of MET pathway inhibitors also continues to be explored. This variant has also been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. Due to conflicting reports of pathogenicity, this variant best characterized as a variant of uncertain significance (VUS) https://www.ncbi.nlm.nih.gov/clinvar/variation/41624/.

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. Nonsynonymous mutations in the MET gene have been rarely described in sarcomas (<2%). The N375K variant has been reported as a somatic variant in two cases of NSCLC. It has been also reported in a single family with familial EGFR-mutant lung adenocarcinoma. This variant lies in the non-kinase domain of the protein. Further functional studies showed this mutation reduced the binding affinity of MET for its ligand, hepatocyte growth factor (HGF), damaging subsequent cellular processes including proliferation, motility and tumorigenicity. In ClinVar it is reported as a germline variant of unknown significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/572621/). The activity of MET inhibitors in tumors with non-kinase domain MET mutations is not yet known. The clinical significance of this mutation in this tumor is uncertain. Clinical correlation is recommended.

MET is a receptor tyrosine kinase that has been shown to frequently be altered (mutation or amplification) in various cancers, leading to overexpression. The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been shown to increase growth factor independent proliferation and motility in vitro in tumor cell lines in some studies. However, the functional effect of T1010I is conflicting, as it has been reported both to have phosphorylation level and transforming capacity similar to wild-type Met protein (PMID: 20670955) This variant has also been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. Due to conflicting reports of pathogenicity, this variant best characterized as a variant of uncertain significance (VUS) (https://www.ncbi.nlm.nih.gov/clinvar/variation/41624/).