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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]
Ultraviolet radiation (UV)
[edit]- Signature 7 has a predominance of C>T substitutions at sites of adjacent pyrimidines (adjacent C or T), with a particularly diagnostic subset being the CC>TT dinucleotide mutation. This pattern arises because the major UV-induced DNA photoproducts join two adjacent pyrimidines; the photoproduct is typically the cyclobutane pyrimidine dimer (CPD).[6] Specificity for C>T appears to be due to the million-fold acceleration of C deamination when it is part of a CPD, with the resulting uracil acting as T.[7][8] CPDs are repaired via transcription-coupled nucleotide excision repair, causing a strong bias for C>T substitutions enriched on the untranscribed DNA strand.[9] The regions of a tumor suppressor protein that are mutationally inactivated in sunlight-related skin cancers are the same as in cancers of organs not exposed to sunlight, but the nucleotide mutated is often shifted a few bases to a site where a CPD could form.[10] Ultraviolet radiation exposure is therefore the proposed underlying mutagenic mechanism of this signature. UV also illustrates a subtlety in interpreting a tumor signature as a mutagen signature: only three-quarters of mutations induced by UV in the laboratory are UV signature mutations because UV also triggers cellular oxidative processes.[2] Therefore even if all mutations in a tumor were caused by UV from sunlight, one quarter of the mutations are expected to not be UV signature mutations. A second carcinogen needn't be invoked to explain those mutations, but a second mutational process is required.
History
[edit]During the 1990s, Curtis Harris at the US National Cancer Institute and Bert Vogelstein at the Johns Hopkins Oncology Center in Baltimore reviewed data showing that different types of cancer had their own unique suite of mutations in p53, which were likely to have been caused by different agents[3][11], such as the chemicals in tobacco smoke or ultraviolet light from the sun.[6][12]
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The biological mutagenesis mechanisms underlying mutational signatures (e.g. COSMIC Signatures 1 to 30) include, but are not limited to:[a][4]
Signature 5 has a predominance of T>C substitutions in the ApTpN trinucleotide context with transcriptional strand bias.[9]
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- ^ 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.
- ^ a b c Brash DE (2015). "UV signature mutations". Photochemistry and Photobiology. 91: 15–26. doi:10.1111/php.12377. PMC 4294947.
- ^ a b Hollstein M, Sidransky D, Vogelstein B, Harris CC (July 1991). "p53 mutations in human cancers". Science. 253 (5015): 49–53. Bibcode:1991Sci...253...49H. doi:10.1126/science.1905840. PMID 1905840.
- ^ a b Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. (August 2013). "Signatures of mutational processes in human cancer" (PDF). Nature. 500 (7463): 415–21. Bibcode:2013Natur.500..415.. doi:10.1038/nature12477. PMC 3776390. PMID 23945592.
- ^ 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: 821-36 e16. doi:10.1016/j.cell.2019.03.001. PMC 6506336.
- ^ a b Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Pontén J (1991). "A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma". Proceedings of the National Academy of Sciences USA. 88: 10124–8. doi:10.1073/pnas.88.22.10124. PMC 52880.
- ^ Cannistraro VJ, Pondugula S, Song Q, Taylor JS (2015). "Rapid deamination of cyclobutane pyrimidine dimer photoproducts at TCG sites in a translationally and rotationally positioned nucleosome in vivo". J Biol Chem. 290 (44): 26597–26609. doi:10.1074/jbc.M115.673301. PMC 4646317.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Jin SG, Pettinga D, Johnson J, Li P, Pfeifer GP (2021). "The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing". Science Advances. 7. doi:10.1126/sciadv.abi6508.
- ^ a b Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, Stratton MR (December 2015). "Clock-like mutational processes in human somatic cells". Nature Genetics. 47 (12): 1402–7. doi:10.1038/ng.3441. PMC 4783858. PMID 26551669.
- ^ Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA, Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash DE (1993). "Mutation hotspots due to sunlight in the p53 gene of non-melanoma skin cancers". Proceedings of the National Academy of Sciences USA. 90: 4216–20. doi:10.1073/pnas.90.9.4216. PMC 46477.
- ^ Olivier M, Hussain SP, Caron de Fromentel C, Hainaut P, Harris CC (2004). "TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer". IARC Scientific Publications (157): 247–70. PMID 15055300.
- ^ Pfeifer GP, Hainaut P (2003). "On the origin of G --> T transversions in lung cancer". Mutation Research. 526 (1–2): 39–43. doi:10.1016/s0027-5107(03)00013-7.
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