Tumour mutational burden (abbreviated as TMB) is a genetic characteristic of tumorous tissue that can be informative to cancer research and treatment. It is defined as the number of non-inherited mutations per million bases (Mb) of investigated genomic sequence,[1] and its measurement has been enabled by next generation sequencing. High TMB and DNA damage repair mutations were discovered to be associated with superior clinical benefit from immune checkpoint blockade therapy by Timothy Chan and colleagues at the Memorial Sloan Kettering Cancer Center.[2]
TMB has been validated as a predictive biomarker with several applications, including associations reported between different TMB levels and patient response to immune checkpoint inhibitor (ICI) therapy in a variety of cancers.[3][4] TMB is also strongly predictive of overall as well as disease-specific survival, independently of cancer type, stage or grade. Patients with both low and high TMB fare notably better than those with intermediate burden.[5]
While both TMB and mutational signatures give us critical information about cancer behaviour, they have different definitions. TMB is defined as the number of somatic mutations/megabase whereas mutational signatures are distinct mutational patterns of single base substitutions, double base substitutions, or small insertions and deletions in tumors.[6] For instance, COSMIC single base substitution signature 1 is characterized by the enzymatic deamination of cytosine to thymine and has been associated with age of an individual.[6]
Scientists postulate that high TMB is associated with an increased amount of neoantigens, which are tumour specific markers displayed by cells.[2][7] An increase in these antigens may then lead to increased detection of cancer cells by the immune system and more robust activation of cytotoxic T-lymphocytes. Activation of T-cells is further regulated by immune checkpoints that can be displayed by cancer cells, thus treatment with ICIs can lead to improved patient survival.[8]
On June 16, 2020 the U.S. Food and Drug Administration expanded the approval of the immunotherapy drug pembrolizumab to treat any advanced solid-tumor cancers with a TMB greater than 10 mutations per Mb and continued growth following prior treatments.[9] This marks the first time that the FDA has approved a drug with its use based on TMB measurements.[10]
Mutations (red marks) in segments of the genome are reflected in proteins produced from them through transcription and translation. Some proteins are fragmented into peptides that can then be presented as antigens on the surface of cell membranes by major histocompatibility complexes (MHCs). If presented antigens accumulate enough mutations, they can bind and activate T-cells which can then initiate immune mediated cell death.
^Merino DM, McShane LM, Fabrizio D, Funari V, Chen S, White JR, et al. (2020). "Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project". J Immunother Cancer. 8 (1): e000147. doi:10.1136/jitc-2019-000147. PMC 7174078. PMID 32217756.
^Kim JY, Kronbichler A, Eisenhut M, Hong SH, van der Vliet HJ, Kang J, et al. (2019). "Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis". Cancers. 11 (11): 1798. doi:10.3390/cancers11111798. PMC 6895916. PMID 31731749.
^Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A, Kaley TJ, Kendall SM, Motzer RJ, Hakimi AA, Voss MH, Russo P, Rosenberg J, Iyer G, Bochner BH, Bajorin DF, Al-Ahmadie HA, Chaft JE, Rudin CM, Riely GJ, Baxi S, Ho AL, Wong RJ, Pfister DG, Wolchok JD, Barker CA, Gutin PH, Brennan CW, Tabar V, Mellinghoff IK, DeAngelis LM, Ariyan CE, Lee N, Tap WD, Gounder MM, D'Angelo SP, Saltz L, Stadler ZK, Scher HI, Baselga J, Razavi P, Klebanoff CA, Yaeger R, Segal NH, Ku GY, DeMatteo RP, Ladanyi M, Rizvi NA, Berger MF, Riaz N, Solit DB, Chan TA, Morris LG (2019). "Tumor mutational load predicts survival after immunotherapy across multiple cancer types". Nature Genetics (2): 202–206. doi:10.1038/s41588-018-0312-8. PMC 6365097. PMID 30643254.
^ abAlexandrov LB, Kim J, Haradhvala NJ, Huang MN, Ng AW, Wu Y, et al. (2020). "The repertoire of mutational signatures in human cancers". Nature. 578 (7793): 94–101. Bibcode:2020Natur.578...94A. doi:10.1038/s41586-020-1943-3. PMC 7054213. PMID 32025018.
^Owada-Ozaki Y, Muto S, Takagi H, Inoue T, Watanabe Y, Fukuhara M, et al. (2018). "Prognostic Impact of Tumour Mutation Burden in Patients with Completely Resected Non-Small Cell Lung Cancer: Brief Report". Journal of Thoracic Oncology. 13 (8): 1217–1221. doi:10.1016/j.jtho.2018.04.003. PMID 29654927. S2CID 4863075.
^Riviere P, Goodman AM, Okamura R, Barkauskas DA, Whitchurch TJ, Lee S, et al. (2020). "High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers". Molecular Cancer Therapeutics. 19 (10): 2139–2145. doi:10.1158/1535-7163.MCT-20-0161. PMC 7541603. PMID 32747422.
^"FDA approves pembrolizumab for adults and children with TMB-H solid tumors". U.S. Food and Drug Administration. 2020. Retrieved February 18, 2021.
^"FDA Approves First Drug for Cancers with a High Tumor Mutational Burden". American Cancer Society. 2020. Retrieved February 18, 2021.
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