The MET gene provides instructions for a protein that signals within cells, influencing processes like cell growth and survival. Changes in this gene, known as mutations, can lead to abnormal cellular behavior, contributing to the development and spread of various diseases. Understanding these mutations is important for tailoring effective treatments.
The MET Gene and Protein
The MET gene, located on chromosome 7, is a proto-oncogene, which can become cancer-promoting if altered. It contains instructions, in segments called exons, for producing the MET protein.
The MET protein is a receptor tyrosine kinase that spans the cell membrane. Its extracellular part binds to a signaling molecule called hepatocyte growth factor (HGF), while its intracellular part has tyrosine kinase activity. This internal portion controls enzymatic activity that regulates cell division and growth.
Normally, the MET protein is involved in embryonic development, organ formation, and tissue repair. When HGF binds to the MET receptor, it triggers signals inside the cell that promote cell proliferation, survival, movement, and the formation of new blood vessels.
Types and Impact of MET Mutations
MET gene alterations can lead to the MET protein becoming abnormally active. This abnormal activity can drive uncontrolled cell growth and proliferation, contributing to cancer.
A MET exon 14 skipping mutation occurs when exon 14’s instructions are skipped during MET protein production. Exon 14 normally allows a protein called CBL to bind to MET for degradation. When skipped, CBL cannot bind, extending the MET protein’s life and causing continuous, excessive signaling that promotes unchecked cell division. These mutations are found in approximately 3-5% of non-small cell lung cancer (NSCLC) cases.
MET amplification involves an increase in MET gene copies, leading to excessive MET protein production and higher signaling. This is observed in about 1-6% of NSCLC patients. Point mutations, single base changes, can also occur in the MET gene, making the MET protein constantly overactive. These contribute to cancers, including non-small cell lung cancer, gastric cancer, and kidney cancer.
Detecting MET Mutations
Identifying MET mutations in patients is an important step in guiding personalized cancer treatment. Various methods are employed, using traditional tissue-based analyses and less invasive blood tests.
Traditional tissue biopsy testing uses techniques such as next-generation sequencing (NGS), which detects multiple mutations across numerous genes, providing a comprehensive genetic profile. Fluorescence in situ hybridization (FISH) detects MET amplifications by visualizing gene copies. Immunohistochemistry (IHC) assesses MET protein overexpression.
Beyond tissue biopsies, liquid biopsy has emerged as a less invasive alternative. This method analyzes circulating tumor DNA (ctDNA) shed by tumor cells in blood plasma. Liquid biopsy identifies genetic alterations, including MET amplifications, for mutation detection, disease monitoring, and assessing treatment response.
Therapeutic Approaches Targeting MET
Targeted therapy focuses on specific molecules involved in cancer growth. For MET mutations, this involves drugs called MET tyrosine kinase inhibitors (TKIs). These inhibitors block the abnormal activity of the mutated MET protein, turning off the “on” switch that drives uncontrolled cell proliferation.
Several MET-selective TKIs are approved for certain cancers, particularly non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations. Examples include capmatinib and tepotinib, which shrink tumors or slow disease progression. These drugs work by binding to the active site of the MET kinase, preventing it from phosphorylating intracellular targets involved in cell growth and angiogenesis.
Therapy choice is guided by the specific MET alteration identified. These targeted therapies provide a precise and effective treatment by directly addressing the cancer’s genetic driver.
Acquired Versus Inherited MET Mutations
MET gene mutations can be acquired during a person’s lifetime (somatic) or inherited from a parent (germline). Most cancer-related MET mutations are somatic, occurring in specific body cells after conception and not passed down to offspring. These acquired mutations are confined to tumor cells, arising from environmental exposures or errors during cell division.
In rare instances, MET mutations are inherited as germline mutations. These mutations are present in every cell from birth and can be passed down through generations. Hereditary papillary renal carcinoma (HPRC) is a rare inherited cancer syndrome linked to activating germline mutations in the MET proto-oncogene. Individuals with HPRC are predisposed to developing multiple, bilateral papillary renal cell carcinomas, often at a younger age. While uncommon, inherited MET mutations imply higher risk for family members and require genetic counseling and surveillance.