Recent clinical studies have identified the tumor mutational burden (TMB) as reliable predictive biomarker for responses to treatment with immune checkpoint blockade (Hellmann et al., 2018). TMB is defined as somatic mutations per megabase (mut/MB).
The higher the numbers of genetic variations within a tumor cell, the more mutated proteins are expressed. These mutated proteins are processed into short fragments (peptides) which are presented on the cell surface of tumor cells. Such mutated peptides are called neoantigens. Neoantigens are highly immunogenic. This means that they are very effectively recognized by immune cells, particularly by T cells. T cells are able to directly eliminate tumor cells upon antigen recognition. Therefore, the higher the numbers of mutations, the higher the chance that neoantigens are presented on tumor cells and thus the more efficient is tumor eradication by T cells.
By sequencing the genes of our panel with high sensitivity, we are able to calculate the TMB. This metric is used to classify tumors into groups with low, medium and high mutational load. Calculation of TMB is part of our medical report. We list the classification of the TMB, as well as the exact mutation rate of the tumor sample. When calculating the TMB, the size of the panel is crucial for the precision of the results. With a size of 2.2 MB, CeGaTs Panel is well above the minimum requirement of 1.5 Mb and ensures a robust estimate of TMB.
MSI (microsatellite instability) is another important parameter for response to immune checkpoint blockade. Microsatellites are small repetitive sequences of DNA located throughout the genome. The size of microsatellites can be altered (microsatellite instability, MSI) due to failures of the DNA mismatch repair machinery.