MTAP Deletion: Its Role as a Biomarker and Cancer Target

Our bodies are made of trillions of cells, each containing genes that instruct it how to grow, function, and divide. Sometimes, a piece of a chromosome housing these genes is accidentally removed in a process called gene deletion. While many such events are harmless, the deletion of certain genes can have significant health consequences.

One such gene is MTAP, or methylthioadenosine phosphorylase. The absence of the MTAP gene is frequently observed in various cancers, making it a useful biomarker—a biological signpost that can guide medical decisions. Understanding how this deletion affects cancer cells opens new possibilities for diagnosis and targeted therapies.

The Role of the MTAP Gene

The MTAP gene holds instructions for producing the enzyme methylthioadenosine phosphorylase. This enzyme works in the purine salvage pathway, a cellular recycling system. Purines are building blocks of DNA and RNA, and this pathway allows the cell to recycle purine components from molecules that are no longer needed.

This process is like a city’s recycling program, which reuses old materials instead of manufacturing new items from raw materials. The MTAP enzyme takes a substance called methylthioadenosine (MTA) and breaks it down to salvage adenine, a purine. This recycled adenine can then be used to create new DNA and other molecules.

This salvage operation runs constantly in healthy cells, ensuring that building blocks for DNA replication and repair are available. The MTAP enzyme facilitates a specific step in this recycling loop. This helps maintain a stable internal environment for the cell to function correctly.

Connection to Cancer Development

The reason MTAP deletion is common in cancer relates to its location, not its function. The MTAP gene resides on chromosome 9, right next to a tumor suppressor gene called CDKN2A. Tumor suppressors act like brakes on a car, preventing cells from dividing out of control, and cancers often disable these systems to grow.

Many cancers delete the section of the chromosome containing CDKN2A to enable unchecked growth. Because the MTAP gene is located so close, it is often removed during this event as collateral damage. This co-deletion is a consequence of the cancer cell’s primary goal of eliminating the CDKN2A tumor suppressor.

The loss of CDKN2A is a driver in cancer development. The accompanying loss of MTAP serves as an indicator that this tumor suppressor is also missing. The result is a cancer cell that has lost its primary braking system, allowing for uncontrolled growth.

Cancers Associated with MTAP Deletion

The co-deletion of MTAP and CDKN2A occurs in a wide range of cancers, making MTAP deletion a common genetic marker. It is prevalent in some of the most aggressive and difficult-to-treat malignancies, including:

• Glioblastoma, an aggressive brain cancer
• Mesothelioma, a cancer linked to asbestos exposure
• Pancreatic cancer, particularly pancreatic ductal adenocarcinoma
• Non-small cell lung cancer
• Bladder cancer
• Soft-tissue sarcomas
• Certain forms of leukemia and lymphoma

The prevalence across such a diverse group of cancers highlights that the removal of the CDKN2A tumor suppressor is a common strategy used by cancer cells. The consistent loss of MTAP provides a shared feature across these distinct diseases.

Therapeutic Strategies and Treatment Implications

The deletion of the MTAP gene creates a vulnerability in cancer cells that can be exploited for treatment. This approach is based on a concept known as synthetic lethality. A healthy cell has multiple ways to perform a function, but a cancer cell with MTAP deletion has lost one method, so a drug blocking the backup pathway can selectively kill cancer cells while leaving healthy cells unharmed.

When a cancer cell lacks the MTAP gene, it cannot use the purine salvage pathway. This forces the cell to depend entirely on a more energy-intensive process called de novo purine synthesis to create DNA building blocks from scratch. Drugs that inhibit this de novo pathway are therefore particularly effective against MTAP-deleted tumor cells.

The loss of the MTAP enzyme also causes a buildup of its substrate, MTA, within the cancer cell. High levels of MTA interfere with other enzymes, notably PRMT5 and MAT2A. This makes the cancer cell highly sensitive to drugs that target these enzymes, and several such inhibitors are now in clinical trials for patients with MTAP-deficient tumors.

Detecting MTAP Deletion

Detecting if a patient’s tumor has an MTAP deletion relies on established laboratory techniques. This information helps oncologists predict a tumor’s behavior and guide treatment decisions. The two primary methods for detection are genomic testing and a protein-based analysis called immunohistochemistry (IHC).

Genomic testing, such as Next-Generation Sequencing (NGS), directly analyzes a tumor’s DNA from a biopsy sample. The NGS platform reads the genetic sequence to identify which genes are present, mutated, or deleted. This method provides definitive confirmation of MTAP gene loss and is often part of broader genomic profiling.

Immunohistochemistry (IHC) offers a complementary approach by checking for the MTAP protein instead of the gene. In this method, thin slices of tumor tissue are treated with antibodies that bind to the MTAP protein, making it visible under a microscope. If the protein is absent in cancer cells but present in healthy tissue, it confirms the functional loss of the gene. IHC is often faster and less expensive than NGS, making it a widely used screening tool.