Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.[1]
The term is used for two distinct concepts, often conflated: mutagen signatures and tumor signatures. Its original use, mutagen signature, referred to a pattern of mutations made in the laboratory by a known mutagen and not made by other mutagens – unique to the mutagen as a human signature is unique to the signer. Uniqueness allows the mutagen to be deduced from a cell's mutations [2] Later, the phrase referred to a pattern of mutations characteristic of a tumor type, although usually not unique to the tumor type nor to a mutagen.[3][4] If a tumor mutational signature matches a unique mutagen mutational signature, it is valid to deduce the carcinogen exposure or mutagenesis process that occurred in the patient's distant past.[2] Increasingly refined tumor signatures are becoming assignable to mutagen signatures.[5]
Deciphering mutational signatures in cancer provides insight into the biological mechanisms involved in carcinogenesis and normal somatic mutagenesis.[6] Mutational signatures have shown their applicability in cancer treatment and cancer prevention. Advances in the fields of oncogenomics have enabled the development and use of molecularly targeted therapy, but such therapies historically focused on inhibition of oncogenic drivers (e.g. EGFR gain-of-function mutation and EGFR inhibitor treatment in colorectal cancer[7]). More recently, mutational signatures profiling has proven successful in guiding oncological management and use of targeted therapies (e.g. immunotherapy in mismatch repair deficient of diverse cancer types,[8] platinum and PARP inhibitor to exploit synthetic lethality in homologous recombination deficient breast cancer).[9]
^Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. (January 2017). "COSMIC: somatic cancer genetics at high-resolution". Nucleic Acids Research. 45 (D1): D777–D783. doi:10.1093/nar/gkw1121. PMC 5210583. PMID 27899578.
^ abBrash DE (2015). "UV signature mutations". Photochemistry and Photobiology. 91 (1): 15–26. doi:10.1111/php.12377. PMC 4294947. PMID 25354245.
^Cite error: The named reference Hollstein1991 was invoked but never defined (see the help page).
^Cite error: The named reference Alexandrov2013 was invoked but never defined (see the help page).
^Kucab JE, Zou X, Morganella S, Joel M, Nanda AS, Nagy E, Gomez C, Degasperi A, Harris R, Jackson SP, Arlt VM, Phillips DH, Nik-Zainal S (2019). "A compendium of mutational signatures of environmental agents". Cell. 177 (4): 821–36 e16. doi:10.1016/j.cell.2019.03.001. PMC 6506336. PMID 30982602.
^Cite error: The named reference Alexandrov2015 was invoked but never defined (see the help page).
^Seow H, Yip WK, Fifis T (March 2016). "Advances in Targeted and Immunobased Therapies for Colorectal Cancer in the Genomic Era". OncoTargets and Therapy. 9 (9): 1899–920. doi:10.2147/OTT.S95101. PMC 4821380. PMID 27099521.
^Chuk MK, Chang JT, Theoret MR, Sampene E, He K, Weis SL, Helms WS, Jin R, Li H, Yu J, Zhao H, Zhao L, Paciga M, Schmiel D, Rawat R, Keegan P, Pazdur R (October 2017). "FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma". Clinical Cancer Research. 23 (19): 5666–5670. doi:10.1158/1078-0432.CCR-16-0663. PMID 28235882.
^O'Neil, Nigel J.; Bailey, Melanie L.; Hieter, Philip (26 June 2017). "Synthetic lethality and cancer". Nature Reviews Genetics. 18 (10): 613–623. doi:10.1038/nrg.2017.47. PMID 28649135. S2CID 3422717.
and 25 Related for: Mutational signatures information
Mutationalsignatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity...
TMB is defined as the number of somatic mutations/megabase whereas mutationalsignatures are distinct mutational patterns of single base substitutions,...
Cambridge in 2014. Alexandrov is known for developing the concept of mutationalsignatures together with Michael Stratton and colleagues at the Wellcome Sanger...
relevant mutationalsignatures associated with BRCA1/BRCA2 deficiency, irrespective of whether these signatures are the dominant mutational process in...
subjects for optimal benefit of specific treatments. Genomic signatureMutationalsignatures Gene expression profiling Gene expression profiling in cancer...
although not all necessarily are. All mutagens have characteristic mutationalsignatures with some chemicals becoming mutagenic through cellular processes...
DNA rearrangements. COSMIC also catalogues mutationalsignatures in human cancer through the COSMIC Signatures group, which represents a collaboration between...
genetic drift. For example, smaller populations with heavy mutational input (high rates of mutation) are prone to increases of genetic variation which lead...
Steven G.; Tan, Patrick; Teh, Bin Tean (7 August 2013). "Genome-Wide MutationalSignatures of Aristolochic Acid and Its Application as a Screening Tool". Science...
context-dependent mutations can be represented in the form of a nonnegative matrix. This matrix can be further decomposed into components (mutationalsignatures) which...
Guan, P.; Weng, W.-H.; Siew, E. Y.; Liu, Y. (2013). "Genome-Wide MutationalSignatures of Aristolochic Acid and Its Application as a Screening Tool". Science...
signature of phylogenetically related genomes is similar. Gene signaturemutationalsignatures Alignment-free sequence analysis Bioinformatics Computational...
DNA polymerase theta is an enzyme that in humans is encoded by the POLQ gene. This polymerase plays a key role in one of the three major double strand...
which a large number of highly patterned basepair mutations occur in a small region of DNA. The mutational clusters are usually several hundred basepairs...
cancer to develop in an individual can be identified by analyzing mutationalsignatures from genomic sequencing of tumor DNA. For example, this can reveal...
cancer-specific research but are not reflected in economics and policy. Mutationalsignatures of various cancers, for example, could reveal further causes of...
Steele, E.J. (2013). "Critical analysis of strand-biased somatic mutationsignatures in TP53 versus Ig genes, in genome -wide data and the etiology of...
Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's...
cross-link where it was shown on the basis of the difference in the mutationalsignatures of the two polymerases, that pol IV and pol V compete for TLS of...
and cancer: Critical analysis of strand-biased and codon-context mutationsignatures". DNA Repair. 45 (2016): 1–2 4. doi:10.1016/j.dnarep.2016.07.001...
D, Shamansky V, et al. (October 2022). "A mitochondria-specific mutationalsignature of aging: increased rate of A > G substitutions on the heavy strand"...
See-Tong; Tan, Patrick; Teh, Bin Tean; Rozen, Steven G. (Dec 2015). "Mutationsignatures implicate aristolochic acid in bladder cancer development". Genome...
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