Tumor Mutational Burden (TMB) is a biological measurement that counts the number of genetic errors, known as mutations, within the DNA of cancer cells. If a cell’s genetic code is an instruction manual, mutations are like typos that can lead to the uncontrolled growth that defines cancer. TMB quantifies these genetic mistakes, providing a score reported as mutations per megabase (mut/Mb) of DNA. This measurement offers a window into the genetic instability of a cancer, a feature that varies widely from one tumor to another.
The Genetic Origins of Mutations in Tumors
The mutations tallied by TMB are somatic, meaning they are acquired during a person’s lifetime and are distinct from inherited mutations passed down from parents. These somatic mutations arise from different sources. Many are simply the result of random errors that occur when a cell makes a copy of its DNA before dividing, as cellular proofreading machinery is not perfect.
Failures in a cell’s DNA repair toolkit are another major cause of mutation buildup. For instance, some tumors have a condition called mismatch repair deficiency (dMMR), where the mechanisms that correct DNA copying errors are broken. This defect leads to a much higher rate of mutations.
External factors, known as mutagens, can also directly damage DNA and increase the mutation rate. Prolonged exposure to ultraviolet (UV) radiation from the sun is a primary driver of mutations in melanoma. Similarly, chemicals found in tobacco smoke are a major cause of the high number of mutations often seen in lung cancers.
Clinical Measurement of TMB
Determining a tumor’s TMB begins with obtaining a sample of the cancerous tissue, usually through a biopsy or from tissue removed during surgery. In the lab, a technology called next-generation sequencing (NGS) is used to analyze its DNA. NGS is a powerful method that reads millions of small DNA fragments simultaneously, allowing for a comprehensive analysis.
This process identifies the mutations present in the cancer cells that are not present in the patient’s normal cells. While the most thorough method, whole exome sequencing (WES), analyzes all protein-coding genes, many clinical tests use more focused NGS panels. These panels examine hundreds of cancer-related genes to estimate the TMB more quickly and cost-effectively.
Significance of High vs. Low TMB
The TMB score categorizes tumors as “TMB-High” or “TMB-Low,” with a score of 10 mutations per megabase often used as a cutoff. The significance of this number lies in how it affects a tumor’s interaction with the immune system. Each genetic mutation has the potential to alter a protein within the cancer cell.
When a mutation changes a protein’s structure, it can create a version the immune system has not seen before, known as a neoantigen. The immune system sees these neoantigens as flags, marking the cancer cells as foreign and targeting them for destruction.
A tumor with a high TMB has more mutations, meaning it is likely to produce a wider variety of these neoantigen flags. This abundance of neoantigens makes the tumor highly visible to immune cells, like T-cells, giving the immune system more targets to attack.
In contrast, a TMB-Low tumor has few mutations and consequently produces very few neoantigens. This lack of flags allows the tumor to appear more like a normal cell, helping it to evade detection and destruction by the immune system.
Predictive Value for Immunotherapy
A tumor’s TMB level is a predictive biomarker for a class of treatments called immune checkpoint inhibitors. These drugs do not attack cancer cells directly but instead empower the patient’s own immune system. T-cells have natural “brakes,” or checkpoints, that prevent them from attacking healthy cells. Some cancers exploit this by displaying proteins that activate these checkpoints, ordering T-cells to stand down.
Immune checkpoint inhibitors function by blocking this interaction, effectively “releasing the brakes” on the T-cells. This allows the immune system to launch a powerful attack against the cancer. Since TMB-High tumors are highly visible to the immune system, they are more likely to be targeted when checkpoint inhibitors unleash T-cells.
This relationship has been observed across multiple cancer types, including melanoma, non-small cell lung cancer, and bladder cancer. In 2020, this connection led the U.S. Food and Drug Administration to approve the checkpoint inhibitor pembrolizumab for any solid tumor with a high TMB that has not responded to other treatments.
TMB is a predictor, not a guarantee of success, as some patients with TMB-Low tumors still benefit from immunotherapy, and not all with TMB-High tumors respond. Oncologists use TMB as one piece of information, often alongside other biomarkers like PD-L1 expression, to guide treatment decisions.