Tumor mutational burden

Tumor Mutational Burden (TMB) is a measure of the number of mutations carried by tumor cells. It is a potential biomarker of immunotherapy response, particularly in the context of checkpoint inhibitor therapies.

Definition

Tumor Mutational Burden is defined as the total number of non-synonymous mutations per megabase of genome examined. Non-synonymous mutations are those that result in a change in the amino acid sequence of the encoded protein. TMB is typically measured using Next-Generation Sequencing (NGS) technologies, which can detect both single nucleotide variants and small insertions and deletions.

Clinical Significance

High TMB has been associated with a better response to immunotherapy in several types of cancer, including non-small cell lung cancer (NSCLC), melanoma, and urothelial carcinoma. The rationale behind this is that a higher number of mutations leads to a greater number of neoantigens, which are more likely to be recognized by the immune system as foreign, thus triggering an immune response.

However, the relationship between TMB and immunotherapy response is not straightforward. Some tumors with low TMB also respond to immunotherapy, and not all tumors with high TMB respond. Therefore, TMB is currently considered as one of several potential biomarkers for immunotherapy response, alongside PD-L1 expression and microsatellite instability (MSI).

Measurement

TMB is typically measured using Next-Generation Sequencing (NGS) technologies. The most common method is whole exome sequencing (WES), which sequences the entire coding region of the genome. However, due to the high cost and complexity of WES, targeted gene panels that sequence a subset of the genome are often used in the clinical setting. These panels must be carefully designed to ensure they accurately capture TMB.

Limitations

There are several limitations to the use of TMB as a biomarker. First, there is currently no standardized method for measuring TMB, leading to variability between different labs. Second, TMB is a static measure that does not capture the dynamic nature of the tumor genome. Finally, TMB does not provide information on the specific mutations present in the tumor, some of which may have direct therapeutic implications.

See Also

• Cancer immunotherapy
• Biomarker (medicine)
• Next-Generation Sequencing
• Neoantigen
• Microsatellite instability