Tumor Mutational Burden (TMB) is a measurement of genetic changes found within cancer cell DNA. It has emerged as an important biomarker in oncology, providing insights that can help guide treatment decisions.
Understanding Tumor Mutational Burden
TMB refers to the quantity of genetic alterations within a tumor’s DNA. These alterations, known as mutations, are changes in the genetic code of cancer cells not present in normal, healthy cells. A high TMB indicates a greater accumulation of these genetic changes within the tumor.
These mutations can arise from various factors, including errors during cell division or exposure to environmental mutagens like ultraviolet light or chemicals found in tobacco. Numerous mutations can lead to the formation of abnormal proteins, termed neoantigens, unique to tumor cells. These neoantigens are recognized by the body’s immune system as foreign, influencing its interaction with the tumor.
Measuring Tumor Mutational Burden
Measuring a tumor’s mutational burden involves analyzing a tumor tissue sample, often obtained through a biopsy. The primary method for this analysis is Next-Generation Sequencing (NGS), a technology allowing comprehensive examination of the tumor’s genetic material. This process sequences the DNA from the tumor sample to identify and count mutations.
While whole exome sequencing (WES), which analyzes all protein-coding regions of the genome, is a comprehensive approach, targeted gene panels are also widely used in clinical settings. These panels focus on specific genes relevant in cancer, providing a more cost-effective and faster way to estimate TMB while maintaining accuracy. Results are reported as mutations per megabase (mut/Mb), indicating mutations found within a million DNA base pairs.
Interpreting Tumor Mutational Burden Results
The results of a TMB test are generally reported as a numerical value, often expressed as mutations per megabase (mut/Mb), which quantifies the density of mutations within the tumor’s DNA. Based on this value, a tumor is typically classified as either “High TMB” or “Low TMB.” A higher number signifies more mutations.
There is no single, universally accepted cut-off value defining high TMB, as it varies depending on cancer type and testing platform. A common threshold for high TMB is 10 mutations per megabase or greater. Some classifications include an “Intermediate TMB” range (e.g., 10-20 mut/Mb), with high TMB often above 20 mut/Mb. Interpreting these results helps clinicians understand the tumor’s genetic landscape.
Significance in Cancer Treatment
Tumor Mutational Burden is an important predictive biomarker in cancer treatment, particularly for guiding immunotherapy. Immunotherapy, which harnesses the body’s own immune system to fight cancer, has shown enhanced effectiveness in tumors with a high mutational burden. The rationale is that tumors with more mutations produce a greater number of unique, abnormal proteins called neoantigens.
These numerous neoantigens make cancer cells more “visible” and recognizable to the immune system, leading to a stronger immune response. Immune checkpoint inhibitors, a type of immunotherapy, work by “releasing the brakes” on immune cells, allowing them to effectively target and eliminate cancer cells. Studies indicate that patients with high TMB experience improved response rates and longer survival when treated with these inhibitors across various cancer types, including melanoma and non-small cell lung cancer. Consequently, TMB testing is increasingly used to guide personalized treatment decisions.