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  • Writer's pictureDženita Omerkić Dautovic, MSc & Dr Edin Hamzić

🧬 💊 MET Gene Mutations and Cancer: What You Need to Know

What Does the MET Gene Do?

The MET gene was discovered in 1984 by Cooper et al. [citation]. The MET gene encodes a protein called hepatocyte growth factor receptor protein (HGFR) or tyrosine-protein kinase Met. 

The MET  is an abbreviation for mesenchymal-epithelial transition factor. 

Throughout this post, the term hepatocyte growth factor receptor (HGFR) protein will be used to denote the product of the MET gene. The HGFR protein is involved in the proliferation, motility, and differentiation processes in normal cells [citation]. 

The official name for this gene is MET proto-oncogene, receptor tyrosine kinase [citation]. 

The MET gene is located on the long arm of chromosome 7 and is roughly 126,191 bases long. 

HGFR protein is a high-affinity receptor tyrosine kinase [citation] (RTK) for hepatocyte growth factor (HGF, also known as Scatter Factor). MET gene is expressed by mesenchymal stem cells, promoting cellular migration and proliferation during tissue repair and wound healing [citation].

The HGFR protein is one of the critical elements in the MET signaling pathway, and it regulates many physiological processes, such as cell proliferation, cell scattering, cell morphogenesis, and cell survival in epithelial and endothelial cells, hematopoietic cells, neurons, melanocytes, and hepatocytes as well as in cytoskeletal function [citation, citation]. The MET signaling pathway is essential for embryogenesis, wound healing, and organogenesis. 

What Are the Key Biological Pathways in Which the MET Gene Is Involved?

The MET gene regulates several distinct biological processes, some of which have already been mentioned in the previous section, such as:

  1. Cell proliferation

  2. Cell scattering

  3. Cell morphogenesis

  4. Cell invasion

  5. Epithelial remodeling, and 

  6. Cell survival

Why Is the MET Gene Important, and for What?

As mentioned above, the MET gene encodes HGFR (c-Met receptor) that initiates activation of the hepatocyte growth factor (HGF) by binding to the plasma membrane.

This activation is essential for cell differentiation, proliferation, and related activities to these biological processes [citation]. Under normal conditions, HGF/ c-Met can mediate embryogenesis, tissue regeneration, wound healing, and the formation of nerves and muscle, which is controlled by the tumor suppressor p53 [citation].

Is MET a Membrane Protein?

Yes, MET is the membrane protein. Isolation of the full-length MET proto-oncogene coding sequence revealed structural features of a membrane-spanning receptor tyrosine kinase [citation].

Where is the MET gene expressed?

MET gene is broadly expressed in the placenta, liver, and 20 other tissues (lung, liver, thyroid, urinary bladder, stomach, lung, gallbladder, colon, kidney, etc) [citation].

Is MET Gene Tumor Suppressor? Is MET a Proto-Oncogene?

The MET gene is not a tumor suppressor, but the MET gene is a protooncogene [citation].

What Is MET Alteration?

Any change affecting the MET gene's genetic code and may alter the protein synthesis is considered MET alteration. 

How and Why Does the MET Gene Become an Oncogene?

MET gene becomes oncogene due to alterations, which include:

  • the MET gene amplification, 

  • point mutations, 

  • gene fusions, 

  • exon 14 skipping mutations, or 

  • protein overexpression.

The MET gene alterations have been reported in many types of carcinoma. These alterations can lead the MET gene to become an oncogene [citation].

Aberrant signaling of MET has a critical role in cancer, and MET is an attractive oncology target [citation].

What Is the Role of the MET Gene in Cancer?

Mutation, overexpression, and aberrant behavior of the MET gene can cause human cancer [citation]. 

Perturbation of the HGF/Met signaling axis leads to enhanced signaling that occurs in a wide range of human cancers. Elevated Met signals are characteristic of aggressive tumors with poor prognosis  [citation].

Hepatocyte growth factor with ligands produced by the MET gene (as mentioned in the preface), can cooperate with other tyrosine kinases. Aberrantly activated signaling pathway (HGF/c-MET) may lead to stimulation of a wide range of down signaling pathways in cancer cells (such as PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/β-catenin). The mentioned processes stimulate the invasion, proliferation, and metastasis of cancer [citation].

What is the link between the MET gene and lung cancer (NSCLC)?

The MET gene mutations associated with non-small cell lung cancer (NSLC) typically occur in the SEMA region (exon 2) and the juxtamembrane (JM) sequence region (in exon 14, and is the cause in 3% of NSLC cancer patients). 

JM domain mutations have been characterized in Small Cell Lung Cancer (SCLC) tissue samples. No kinase domain mutations have been identified in lung. Still, somatic and germline mutations have been reported in papillary renal cell carcinoma and hereditary papillary renal cell carcinoma, respectively [citation].

In normal MET signaling, in the absence of mutation related to exon 14, the receptor is activated, internalized and degraded. Mutation in exon 14 results in loss of c-Cbl binding site, decreased ubiquitination and impaired receptor degradation leading to increased MET gene signaling [citation].

N375S is detected as a germline mutation in patients with non-small cell lung cancer (NSCLC) [citation]. 

Resistance to epidermal growth factor receptor (EGFR) inhibitors is known to occur in patients with lung cancer simulated by MET gene expression. However, inhibition of both maximizes the inhibitory effect on lung cancer [citation].

Hepatocyte growth factor with its receptor (HFG/MET) mediates cascades that play a key role in tumorigenesis [citation]. But, more about that in the coming article where we will explain this in more detail.

Mutations in the MET gene have been associated with multiple types of cancers such as [citation]:

  1. Lung cancer

  2. Renal cell carcinoma

  3. Ovarian, kidney, liver, head and neck, thyroid, and prostate cancer 

  4. Sarcomas

  5. Hematologic malignancies

  6. Melanoma, and 

  7. Central nervous system tumors

As it goes with genes, they can have mutations that lead to changes in the protein that they encode which further leads to that given protein to change its function in different ways by being more or less active or inactive. These changes in protein function further lead to cause or can be associated with specific conditions and diseases.

What Are Key Mutations in the MET Gene?

Mutations of the MET gene are reported in its three main domains: 

  1. Extracellular semaphorin (SEMA) domain (exon 2)

  2. Juxtamembrane domain (exon 14/15) and 

  3. Tyrosine kinase domain [citation].

Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers [citation].

MET mutations are reported in small percentages in a variety of cancers. 

Certain are found to be germline, such as in the case of papillary renal carcinoma (Y1248H).

Mutations related to Lung adenocarcinoma:

  • N375S 

  • R988C

  • T1010I

.  Thyroid carcinoma is related to N375S and T1010I (Medullary carcinoma) mutations. N375S, T1010I related to ovary carcinoma [citation]. 

Interestingly, it is documented that trisomy of chromosome 7 occurs in 95% of sporadic papillary renal carcinoma. On chromosome 7 are found both MET and HGF/SF genes. In 100% tumor samples of patients with hereditary papillary renal carcinoma,  nonrandom duplication of mutant MET allele is revealed [citation].

What is a MET mutation most commonly detected in cancers?

N375S, MET point mutation, is most commonly detected in cancers. The mutation that results in a change from Asn (Asparagine) to Ser (Serine) at codon 375. There is a wide range of cancers related to this specific mutation: lung, colorectal carcinoma, breast cancer, ovary cancer [citation], thyroid, uterine, endometrioid carcinoma, and squamous cell carcinoma (Tyr1248C and Tyr1253) [citation]; and many more. 

In this regard, it is necessary to mention the importance of the specificity of all the mentioned tumors as well as other mutations associated with the same, and there are also co-mutations detected in addition to the said point mutation. 

Also, the N375S mutation is detected as a germline mutation in patients with non-small cell lung cancer (NSCLC) [citation].

Another common mutation is T1010I (change from Threonine to Isoleucine at codon 1010) [citation].

What is MET gene amplification?

Overexpressions and mutations of the MET gene are reported to be common in tumor clones with the potential to spread due to extra copies of the MET gene [citation]. For example, in colorectal cancer, overexpression is related to more advanced stages and metastases in the liver and lymph nodes [citation]. 

In NSCLC, overexpression of the MET gene is detected in 25-75% patients [citation]. Also, overexpression is detected in patients with colorectal cancer [citation], clear cell ovarian cancer [citation], breast cancer [citation] etc.

How are genes amplified? How is MET amplification detected?   

Gene amplification refers to an increase in the copy of a particular gene. Southern blot, polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH) are some of the techniques used for MET amplification detection.

What is exon skipping? How does exon skipping work? 

Exon skipping is a form of RNA fusion used to cause cells to "skip" over mismatched parts of the genetic code, leading to a truncated but still functional protein despite a genetic mutation.

Exon skipping can be used as gene therapy in some diseases, but it presents a critical part of personalized medicine. Exon skipping is a treatment approach for people with Duchenne muscular dystrophy (DMD), which is caused by certain genetic mutations. Skipping or masking exons can result in shorter but functional protein, in this case, dystrophin protein. FDA has approved four exon skipping therapies for this disease [citation].

What mutation causes exon skipping?

Exon 14 skipping mutation is firstly discovered in kidney samples from mice and ten years later found in human NSCLC tissues due to somatic mutation [citation].

The mutation leads to deletion of the entire juxtamembrane amino acid, and it can be the result of insertion, indels, point mutation, and deletion that disrupt consensus sequences such as branch sites, and polypyrimidine tracts, splice acceptors, and splice donor sites for RNA splicing. 

All mentioned aberrations cause mis-splicing of MET exon 14, which results in abnormal MET protein lacking the CBL-binding site [citation].

Exon14 skipping (METex14+) results in constitutive activation and a unique subset of non-small cell lung cancers (NSCLC) as a result of genome alteration of mesenchymal-epithelial transition receptor tyrosine kinase (MET) [citation].

What are MET mutations that lead to ​​the MET exon 14 skipping?

There are many types of mutations that lead to MET exon 14 skipping: insertion, indels, point mutation, and deletion. Point mutations are the most common. There are more than 500 types of reported mutations related to MET exon 14 skipping (Research-based on mutation analysis from 1387 patients) [citation] [citation].

Why the MET exon-14 skipping is important?

MET exon 14 skipping is a potential driver alteration in lung cancer targetable. MET exon14 skipping is present in up to 3% of NSCLCs patients [citation].

What is the association between the MET exon 14 skipping and cancer?

MET exon skipping is present in about 3% non-small cell lung cancers patients. MET amplification is mechanism of EGFR resistance in NSCLC cancer patients [citation].

What are the FDA-approved tests for detecting MET exon 14 skipping?

It is known that NGS is used in both laboratory-developed tests (LDTs) and FDA-approved oncology companion diagnostics (CDx), but there are also reported some limitations regarding lack of adaptability because NGS detects restricted hotspots. There are challenges to incorporating these in research for a better understanding of cancer background or future discoveries [citation].

Gem ExTra detects single nucleotide variants (SNV), indels, focal copy number alterations (CNA), TERT promoter region, as well as tumor mutation burden (TMB) and microsatellite instability (MSI) status [citation]. 

(Because there are more than 500 aberrations that can cause MET exon 14 skipping, some countries are working on easier ways of detection, for example Japan. By multiplex PCR detection method scientists are detecting MET mutations from liquid samples. They also reported better results regarding sensitivity, with RNA-based samples.) [citation].

What is MET CEP7 ratio?

MET/CEP7 ratio is useful as a prognostic marker or as an indication for MET inhibitor therapy.

MET signaling pathway is promising target in patient with NSCLC. MET/CEP7 (centromere of chromosome 7) dual-color  fish probe is used to detect MET amplification, regarding to gene copy number or MET/CEP7 ratio.

There are criteria related to this: low (MET/CEP7 ratio, 1.8-2.2), intermediate (MET/CEP7 ratio, > 2.2 to < 5), and high (MET/CEP7 ratio, ≥5 [citation].

The MET Inhibitors: What type of drug is Tabrecta (capmatinib)?

Tabrecta (capmatinib) is an oral, small molecule mesenchymal-epithelial transition (MET) inhibitor being developed by Novartis Oncology. Capmatinib targets and selectively binds to MET, including the mutant variant produced by exon 14 skipping, and inhibits cancer cell growth driven by the mutant MET variant [citation].

In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET exon 14 skipping dawned a new era for MET-targeted therapy. These drugs yielded progression-free survival of 5.4-12.4 months in clinical trials [citation]. Capmatinib activity has been reported to reduce ovarian cancer cell proliferation [citation].

How does Tabrecta (capmatinib) work?

Capmatinib (INC280) blocks c-Met phosphorylation and the activation of key downstream molecules in c-Met-dependent tumor cell lines, causing mitochondrial membrane depolarization and DNA repair. Thereby, capmatinib potently inhibits tumor cell proliferation and migration, inducing apoptosis [citation].

When Tabrecta (capmatinib) is indicated to be used?

Tabrecta is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC). Novartis Pharmaceuticals is performing clinical phase II trials using oral capmatinib combined with gefitinib for NSCLC patients with c-Met amplification [citation].

The use of combinations of drugs to avoid resistance induced by the utilization of a single drug might become a major priority for researchers developing novel c-Met inhibitors.

What is the relation between Tabrecta (capmatinib) and the MET exon 14 skipping?

Capmatinib demonstrated anti-tumor activity in human lung cancer with MET exon 14 skipping mutation or MET amplification, as well as in liver cancer with MET amplification. Also, it is reported that capmatinib restores sensitivity to EGFR inhibitors in EGFR-mutant NSCLC cell lines with acquired resistance to EGFR inhibitors [citation].

What is the FDA-approved genetic testing used for detecting the MET exon 14 skipping and, consequently use of Tabrecta (capmatinib)?

The US FDA has approved the Foundation®OneCDx (F1CDx) next-generation, sequencing-based in vitro diagnostic device for the detection of MET single nucleotide variants (SNVs) that lead to MET exon 14 skipping in patients with NSCLC that may benefit from Capmatinib [citation].


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