What is mutational load and how does it apply to immunotherapy?
Several mutations occur through deleterious variations of the genome. The accumulation of deleterious alleles is referred to as the mutation load, and the total number of somatic mutations per coding area can be monitored in both tumor and healthy cells using next-generation sequencing (NGS) technology. Mutational burden varies among tumor types and reflects the diversity of exposure to DNA damage and repair mechanisms among tumor populations. The mutational load is measured using whole-exome sequencing, but the high costs and time needed to sequence the entire genome requires researchers to home in on regions prone to mutations. Tumor mutational load is a strong determinant of response to immunotherapy. Metastatic melanoma patients with a higher mutational load responded to monoclonal antibody immunotherapy directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with higher clinical benefit.1 Analyzing the mutational load in immune cells also provides insights into impaired tumor infiltration, and effective immunotherapy measures can be designed to compensate for these deficiencies.2
References:
1. E.M. Van Allen et al, "Genomic Correlates of Response to CTLA-4 Blockage in Metastatic melanoma," Science 350(6257): 207-211, 2015.
2. B. Li et al, "Landscape of Tumor-Infiltrating T Cell Repertoire of Human Cancers," Nat Genet 48: 725-732, 2016.
References:
1. E.M. Van Allen et al, "Genomic Correlates of Response to CTLA-4 Blockage in Metastatic melanoma," Science 350(6257): 207-211, 2015.
2. B. Li et al, "Landscape of Tumor-Infiltrating T Cell Repertoire of Human Cancers," Nat Genet 48: 725-732, 2016.