What Is Mutation Burden? Its Role in Genetics and Disease

Mutation burden, often called tumor mutational burden (TMB), is a measure of the total number of mutations present in the DNA of a specific group of cells, such as a tumor. This genetic characteristic provides information about how diseases like cancer might develop and progress. A higher mutation burden can influence how a disease behaves and how it might respond to certain treatments.

In cancer, the accumulation of mutations is a core aspect of the disease’s development. The concept serves as a biomarker to predict patient outcomes and guide therapeutic strategies, making it a focus in personalized medicine.

The Origins of Genetic Mutations

Genetic mutations arise from various sources and are categorized based on when and where they occur. Somatic mutations happen in the body’s cells during a person’s life. These mutations affect only the individual, are not passed on to children, and are a primary driver of cancer development as they can cause cells to grow uncontrollably.

Another class is germline mutations, which are present in the egg or sperm cells. These changes are heritable and can be passed from parent to offspring, meaning they will be present in every cell of the child’s body. While a smaller contributor to the total mutation count in a tumor compared to somatic events, inherited mutations can predispose an individual to certain diseases, including specific types of cancer.

The processes causing these mutations can be internal or external. Endogenous factors originate from within the cell itself, such as errors made during DNA replication or the spontaneous chemical degradation of DNA. These events introduce mutations like point mutations, where one DNA base is swapped for another, or insertions and deletions.

External, or exogenous, factors also contribute to the mutation count. These mutagens are environmental agents that damage DNA. For instance, chemicals found in tobacco smoke and certain industrial pollutants can directly alter DNA, increasing the mutation burden in exposed tissues.

Measuring Mutation Accumulation

To quantify the number of mutations within a cell population, scientists employ advanced sequencing technologies. A prominent method is Whole Exome Sequencing (WES), which focuses on sequencing the exome—the protein-coding regions of genes. Since the exome constitutes only 1-2% of the genome but harbors most known disease-causing mutations, WES is an efficient approach for identifying a large number of relevant mutations.

For a more exhaustive analysis, Whole Genome Sequencing (WGS) sequences the entire genome, including both coding and non-coding regions. While more expensive and computationally intensive, WGS offers the most complete picture of all mutations present. This can be useful in research for discovering novel mutations and understanding the broader landscape of genomic instability.

In many clinical scenarios, a focused approach called targeted gene panel sequencing is used. This method analyzes a specific set of genes known to be associated with a particular disease, such as cancer. Targeted panels are faster and require less DNA, making them practical for routine diagnostic use. The final mutation burden is reported as the number of mutations per megabase (Mut/Mb) of DNA sequenced, providing a standardized metric for comparison.

Clinical Relevance of Mutation Burden

The measurement of mutation burden has applications in clinical practice, especially in oncology. It serves as a biomarker to predict how a patient might respond to certain treatments, particularly immunotherapies. This predictive capacity is a tool in tailoring cancer therapy to a patient’s tumor, a practice known as precision medicine.

A high tumor mutation burden (TMB) is associated with a better response to immunotherapy drugs called immune checkpoint inhibitors. These drugs work by releasing the natural brakes on the immune system, allowing it to attack cancer cells more effectively. A high number of mutations can lead to the production of abnormal proteins, known as neoantigens, on the surface of cancer cells.

These neoantigens act as flags that make the tumor cells appear foreign to the immune system, providing more targets for T-cells to identify. When a patient with a high-TMB tumor receives an immune checkpoint inhibitor, their re-activated immune system has a greater chance of mounting an effective anti-tumor response. This correlation has been observed across various cancer types, including melanoma and non-small cell lung cancer.

Beyond predicting treatment response, mutation burden can also have prognostic value, offering insights into the likely course of the disease. In some cancers, a high TMB is linked to different survival rates, independent of the treatment received. The specific relationship between TMB and prognosis can vary between cancer types, highlighting the complex role that genomic instability plays.

Variability in Mutation Burden

The number of mutations found in a tumor varies considerably across cancer types and even between individuals with the same cancer. This variability results from multiple factors, including the source of the mutations and the body’s ability to repair DNA damage. These factors help explain why some cancers are more genetically complex than others.

Different cancer types exhibit a wide range of mutation burdens. For example, melanomas, which are often caused by extensive exposure to UV radiation, tend to have a very high TMB. In contrast, many pediatric cancers and certain types of leukemia show a low TMB, as they are not linked to the same degree of long-term mutagen exposure.

An individual’s inherent ability to repair DNA damage is another source of variation. Some people have inherited conditions, such as Lynch syndrome, that impair their DNA mismatch repair systems. This deficiency leads to a much higher rate of mutation accumulation, resulting in a high TMB across various tumor types.

Other factors also contribute to the differences observed. The type and duration of exposure to a mutagen, like the number of years a person has smoked, can directly influence the mutation count in lung cancer. Age is also a factor, as mutations accumulate over a lifetime. The mutation burden can even vary within a single tumor, a phenomenon known as intratumor heterogeneity.