What is the MET or c-MET biomarker?

MET is a gene that encodes a protein called c-MET. MET is the mesenchymal-epithelial transition factor gene, and the gene and the protein play a role in cell growth, cell survival, and cell migration. MET is a part of a cell signaling system and works as a receptor, which means it receives messages from another protein called HGF (hepatocyte growth factor). Because of this, c-MET is sometimes called the HGF receptor. c-MET is a type of protein called a receptor tyrosine kinase.

What is MET or c-MET dysregulation?

Abnormalities in the MET gene or in c-MET protein expression are called MET dysregulation. MET dysregulation includes:

• MET gene amplification – too many copies of the MET gene
• MET gene mutation – a change in the DNA sequence of the MET gene
• c-MET protein overexpression – too much of the c-MET protein is made

c-MET protein overexpression can be due to various genetic factors including gene amplification, gene mutation, or through gene expression regulation, which are cell processes that affect when, where, and how much a gene is expressed but do not change the genetic code itself.  

When MET dysregulation occurs, it can cause cancer by making cells grow and survive when they shouldn’t. Genes, like MET, that can cause normal cells to become tumor (tumour) cells are called oncogenes. Oncogenes can act like an “on switch” for cancer. When the switch changes in the wrong way, it can make cells grow out of control. MET dysregulation can also help cancer cells spread to other parts of the body, because of MET's role in cell migration. This is called tumor invasion (spread to nearby sites) and tumor metastasis (spread to distant sites in the body).

MET or c-MET dysregulation is important in colorectal cancer, occurring in 15-81% of these cancers across different studies. It is also a factor in other solid tumors like non-small cell lung cancer (NSCLC), medullary thyroid carcinoma (MTC), renal cell carcinoma, gastric cancer, gastroesophageal adenocarcinoma, and pancreatic ductal adenocarcinoma.  

The changes in MET that are related to colorectal cancer are not hereditary, meaning they are not passed from parents to children.

How is the c-MET biomarker tested?

c-MET status is usually tested in a tumor cell biopsy sample. c-MET testing is usually performed on a sample of primary tumor. c-MET status results from testing a sample of tumor metastasis  can be different from primary tumor results in some cases.  

c-MET status can be tested with several laboratory methods, including  

• IHC (Immunohistochemistry): Uses special antibodies to detect the c-MET protein in the tumor tissue. A chemical makes the protein visible under a microscope.
• FISH (Fluorescence In Situ Hybridization): Uses fluorescent DNA pieces to see if there are changes in the MET gene in the tumor.
• NGS (Next-Generation Sequencing): A method to read many DNA sequences at once to find gene changes.

IHC is a method of analyzing proteins in a tissue biopsy by adding an antibody probe created in the laboratory that will stick or attach to the protein (antigen) of interest, in this case c-MET. The antibody probe is also bound to a chemical compound that makes it visible under a microscope. This can be used to measure the amount of c-MET protein by looking at the amount of the visible antibody probe bound to it.

For the FISH method, probe DNA including the MET gene is created in the laboratory and bound to fluorescent compounds. The fluorescent DNA probe is then added to a sample of tumor DNA. Matching segments of DNA will attach to each other and appear fluorescent. This allows the laboratory to see the similarities and differences in the probe DNA and the tumor DNA.

c-MET status may be tested in a blood sample by examining circulating tumor DNA (ctDNA) for MET gene changes. This is called a liquid biopsy. MET can also be analyzed for mutations in tumor tissue. MET can be tested individually, or as part of a multiple gene panel using next-generation sequencing (NGS). Next-generation sequencing is a method of reading the pattern of many DNA samples at the same time. ‍

What do my MET or c-MET test results mean?

Your test results will differ based on the type of testing you had.  

If you had c-MET protein testing, such as immunohistochemistry (IHC), your results may be reported as “normal” or “high”. Normal c-MET expression is sometimes reported as “c-MET negative”. High c-MET expression is sometimes reported as “c-MET positive”.

If you had MET gene testing via fluorescence in situ hybridization (FISH), your results may be reported as “negative” or “positive”. Negative means that there is no detected MET gene abnormality. Positive means that a MET gene change is present.

If you had MET gene testing via next-generation sequencing (NGS), your result will be reported as “MET wild-type” or “MET mutant”. MET wild-type, sometimes abbreviated MET-WT, means there is no mutation in the MET gene. MET mutant means there is a mutation (abnormality) in the MET gene sequence.

How does my c-MET status impact my treatment?

If your colorectal cancer has normal c-MET expression (c-MET negative), no MET gene amplification, or no MET gene mutation (wild-type)

• Targeted therapy, such as HER2 inhibitors or EGFR inhibitors, will be guided by other biomarker testing results.
• Immunotherapy will be guided by other biomarker testing results, such as microsatellite instability (MSI-High).
• Treatment options also include traditional chemotherapy combinations, such as FOLFOX, FOLFIRI, and CAPOX.  

If your colorectal cancer has high c-MET expression, MET gene amplification, or a MET gene mutation causing high c-MET expression (mutant)

• There are ongoing clinical trials for MET inhibitor treatments targeted to colorectal cancers with high c-MET expression or MET mutations. Talk to your healthcare team about whether you could benefit from a clinical trial.
• Immunotherapy will be guided by other biomarker testing results, such as microsatellite instability (MSI-High).
• Further targeted therapy options will be determined by the results of other biomarker testing.
• Treatment options also include traditional chemotherapy combinations, such as FOLFOX, FOLFIRI, and CAPOX.   

Who should be tested for c-MET?

All patients with stage IV / metastatic colorectal cancer (mCRC) should be tested for the c-MET (MET) biomarker.