Cancers bear many thousands of mutations that are the product of the biological perturbations or mutational processes that have occurred throughout the development of the disease.
Each mutational process leaves its own characteristic mark of mutations, which is referred to as the mutational signature, on the cancer genome.
Mutational signatures are identifiable and quantifiable using mathematical models.
Detailed analyses of mutational signatures can determine the DNA damaging components as well as the DNA repair and replicative pathways that have been operative in cancer or that have gone awry.
Historical mutational processes give insights into the aetiology of a cancer, whereas ongoing mutational processes might act as biomarkers or targets for treatment.
The collective somatic mutations observed in a cancer are the outcome of multiple mutagenic processes that have been operative over the lifetime of a patient. Each process leaves a characteristic imprint — a mutational signature — on the cancer genome, which is defined by the type of DNA damage and DNA repair processes that result in base substitutions, insertions and deletions or structural variations. With the advent of whole-genome sequencing, researchers are identifying an increasing array of these signatures. Mutational signatures can be used as a physiological readout of the biological history of a cancer and also have potential use for discerning ongoing mutational processes from historical ones, thus possibly revealing new targets for anticancer therapies.
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Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009). This is an overview of cancer genomes with a description of various types of somatic mutations acquired during the multistep process of cancer development.
Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012). This study presents catalogues of somatic mutations from 21 breast cancers, the respective mutational signatures of which were extracted by mathematical methods.
Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).
Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).
Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007). This study shows the prevalence of somatic mutations in human cancer genomes, which indicates that most of the mutations do not drive oncogenesis. Nevertheless, it provides evidence for driver mutations that are actively involved in tumour development.
Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).
Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).
Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). In this study, >20 distinct mutational signatures have been extracted from several cancer types, which shows the presence of the APOBEC-mediated signature in various cancers.
Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).
Pfeifer, G. P. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435–7451 (2002).
Ellegren, H., Smith, N. G. & Webster, M. T. Mutation rate variation in the mammalian genome. Curr. Opin. Genet. Dev. 13, 562–568 (2003).
Pfeifer, G. P., You, Y. H. & Besaratinia, A. Mutations induced by ultraviolet light. Mutat. Res. 571, 19–31 (2005).
Lutsenko, E. & Bhagwat, A. S. Principal causes of hot spots for cytosine to thymine mutations at sites of cytosine methylation in growing cells. A model, its experimental support and implications. Mutat. Res. 437, 11–20 (1999).
Nikolaev, S. I. et al. A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas. Cancer Res. 72, 6279–6289 (2012).
Pham, P., Bransteitter, R., Petruska, J. & Goodman, M. F. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424, 103–107 (2003).
Landry, S., Narvaiza, I., Linfesty, D. C. & Weitzman, M. D. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep. 12, 444–450 (2011).
Suspene, R. et al. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proc. Natl Acad. Sci. USA 108, 4858–4863 (2011).
Taylor, B. J. et al. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. Elife 2, e00534 (2013). This paper shows that kataegis observed in the breast cancer genome can stem from AID- or APOBEC-mediated cytidine deamination in the proximity of DNA breaks.
Stephens, P. et al. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nature Genet. 37, 590–592 (2005).
Burns, M. B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370 (2013).
Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genet. 45, 970–976 (2013).
Nik-Zainal, S. et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nature Genet. 46, 487–491 (2014).
Byeon, I. J. et al. NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity. Nature Commun. 4, 1890 (2013).
Holtz, C. M., Sadler, H. A. & Mansky, L. M. APOBEC3G cytosine deamination hotspots are defined by both sequence context and single-stranded DNA secondary structure. Nucleic Acids Res. 41, 6139–6148 (2013).
Karran, P. & Lindahl, T. Hypoxanthine in deoxyribonucleic acid: generation by heat-induced hydrolysis of adenine residues and release in free form by a deoxyribonucleic acid glycosylase from calf thymus. Biochemistry 19, 6005–6011 (1980).
Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).
Hussain, S. P., Hofseth, L. J. & Harris, C. C. Radical causes of cancer. Nature Rev. Cancer 3, 276–285 (2003).
Evans, M. D., Dizdaroglu, M. & Cooke, M. S. Oxidative DNA damage and disease: induction, repair and significance. Mutat. Res. 567, 1–61 (2004).
Oikawa, S. & Kawanishi, S. Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett. 453, 365–368 (1999).
Oikawa, S., Tada-Oikawa, S. & Kawanishi, S. Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening. Biochemistry 40, 4763–4768 (2001).
Cadet, J., Sage, E. & Douki, T. Ultraviolet radiation-mediated damage to cellular DNA. Mutat. Res. 571, 3–17 (2005).
Hendriks, G. et al. Transcription-dependent cytosine deamination is a novel mechanism in ultraviolet light-induced mutagenesis. Curr. Biol. 20, 170–175 (2010).
Schiltz, M. et al. Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine) phosphoribosyltransferase gene in repair-deficient Chinese hamster V-H1 cells. Carcinogenesis 20, 2279–2285 (1999).
Wiseman, R. W., Miller, E. C., Miller, J. A. & Liem, A. Structure–activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J x C3H/HeJ F1 mice. Cancer Res. 47, 2275–2283 (1987).
Papadopoulo, D., Laquerbe, A., Guillouf, C. & Moustacchi, E. Molecular spectrum of mutations induced at the HPRT locus by a cross-linking agent in human cell lines with different repair capacities. Mutat. Res. 294, 167–177 (1993).
Yang, S. C., Lin, J. G., Chiou, C. C., Chen, L. Y. & Yang, J. L. Mutation specificity of 8-methoxypsoralen plus two doses of UVA irradiation in the hprt gene in diploid human fibroblasts. Carcinogenesis 15, 201–207 (1994).
Feldmeyer, N. et al. Further studies with a cell immortalization assay to investigate the mutation signature of aristolochic acid in human p53 sequences. Mutat. Res. 608, 163–168 (2006).
Krokan, H. E., Standal, R. & Slupphaug, G. DNA glycosylases in the base excision repair of DNA. Biochem. J. 325, 1–16 (1997).
Caldecott, K. W. Single-strand break repair and genetic disease. Nature Rev. Genet. 9, 619–631 (2008).
Robertson, A. B., Klungland, A., Rognes, T. & Leiros, I. DNA repair in mammalian cells: base excision repair: the long and short of it. Cell. Mol. Life Sci. 66, 981–993 (2009).
An, Q., Robins, P., Lindahl, T. & Barnes, D. E. C→T mutagenesis and γ-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases. EMBO J. 24, 2205–2213 (2005).
Smart, D. J., Chipman, J. K. & Hodges, N. J. Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2′-deoxyguanosine. DNA Repair (Amst.) 5, 1337–1345 (2006).
Nouspikel, T. DNA repair in mammalian cells: nucleotide excision repair: variations on versatility. Cell. Mol. Life Sci. 66, 994–1009 (2009).
Bohr, V. A., Smith, C. A., Okumoto, D. S. & Hanawalt, P. C. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 40, 359–369 (1985).
Poon, S. L. et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci. Transl Med. 5, 197ra101 (2013).
Guo, J., Hanawalt, P. C. & Spivak, G. Comet-FISH with strand-specific probes reveals transcription-coupled repair of 8-oxoguanine in human cells. Nucleic Acids Res. 41, 7700–7712 (2013).
Pena-Diaz, J. & Jiricny, J. Mammalian mismatch repair: error-free or error-prone? Trends Biochem. Sci. 37, 206–214 (2012).
Jiricny, J. The multifaceted mismatch-repair system. Nature Rev. Mol. Cell Biol. 7, 335–346 (2006).
Tiraby, G., Fox, M. S. & Bernheimer, H. Marker discrimination in deoxyribonucleic acid-mediated transformation of various Pneumococcus strains. J. Bacteriol. 121, 608–618 (1975).
Shibata, D., Peinado, M. A., Ionov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nature Genet. 6, 273–281 (1994).
McCulloch, S. D. & Kunkel, T. A. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res. 18, 148–161 (2008).
Shevelev, I. V. & Hübscher, U. The 3′–5′ exonucleases. Nature Rev. Mol. Cell Biol. 3, 364–376 (2002).
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Cancer Genome Atlas Research Network et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).
Kane, D. P. & Shcherbakova, P. V. A common cancer-associated DNA polymerase ε mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res. 74, 1895–1901 (2014).
Roberts, J. D. & Kunkel, T. A. Fidelity of a human cell DNA replication complex. Proc. Natl Acad. Sci. USA 85, 7064–7068 (1988).
Bester, A. C. et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145, 435–446 (2011).
Jones, R. M. et al. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene 32, 3744–3753 (2013).
Petermann, E., Woodcock, M. & Helleday, T. Chk1 promotes replication fork progression by controlling replication initiation. Proc. Natl Acad. Sci. USA 107, 16090–16095 (2010).
Sale, J. E., Lehmann, A. R. & Woodgate, R. Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nature Rev. Mol. Cell Biol. 13, 141–152 (2012). This is a review on our current understanding of translesion synthesis and the associated Y-family DNA polymerases.
Knobel, P. A. & Marti, T. M. Translesion DNA synthesis in the context of cancer research. Cancer Cell. Int. 11, 39 (2011).
Klarer, A. C. & McGregor, W. Replication of damaged genomes. Crit. Rev. Eukaryot. Gene Expr. 21, 323–336 (2011).
Strauss, B. S. The “A” rule revisited: polymerases as determinants of mutational specificity. DNA Repair (Amst.) 1, 125–135 (2002).
Puente, X. S. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).
Kunz, B. A., Straffon, A. F. & Vonarx, E. J. DNA damage-induced mutation: tolerance via translesion synthesis. Mutat. Res. 451, 169–185 (2000).
Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).
Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363, 558–561 (1993).
Bhattacharyya, N. P., Skandalis, A., Ganesh, A., Groden, J. & Meuth, M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc. Natl Acad. Sci. USA 91, 6319–6323 (1994).
Karran, P. Microsatellite instability and DNA mismatch repair in human cancer. Semin. Cancer Biol. 7, 15–24 (1996).
Kuraguchi, M. et al. Tumor-associated Apc mutations in Mlh1−/− Apc1638N mice reveal a mutational signature of Mlh1 deficiency. Oncogene 19, 5755–5763 (2000).
Weinstock, D. M., Brunet, E. & Jasin, M. Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nature Cell Biol. 9, 978–981 (2007).
Yun, M. H. & Hiom, K. CtIP–BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459, 460–463 (2009).
Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).
Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).
Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).
Davies, A. A. et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol. Cell 7, 273–282 (2001).
Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009). This study analyses somatic rearrangements in the breast cancer genome using paired-end sequencing strategy, which reveals that these rearrangements are mostly intrachromosomal.
Nussenzweig, A. & Nussenzweig, M. C. Origin of chromosomal translocations in lymphoid cancer. Cell 141, 27–38 (2010).
Groth, P. et al. Homologous recombination repairs secondary replication induced DNA double-strand breaks after ionizing radiation. Nucleic Acids Res. 40, 6585–6594 (2012).
Arnaudeau, C., Lundin, C. & Helleday, T. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J. Mol. Biol. 307, 1235–1245 (2001).
Riballo, E. et al. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to γ-H2AX foci. Mol. Cell 16, 715–724 (2004).
Rothkamm, K., Kruger, I., Thompson, L. H. & Lobrich, M. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol. Cell. Biol. 23, 5706–5715 (2003).
Saleh-Gohari, N. & Helleday, T. Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cells. Nucleic Acids Res. 32, 3683–3688 (2004).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This is the first study to characterize chromothripsis in a human cancer genome.
Klein, I. A. et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147, 95–106 (2011).
Chiarle, R. et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147, 107–119 (2011).
Hakim, O. et al. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 484, 69–74 (2012).
Ng, C. K. et al. The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer. J. Pathol. 226, 703–712 (2012).
Costantino, L. et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343, 88–91 (2014). This paper reports a role of DNA Pol δ in BIR repair.
Haber, J. E. Lucky breaks: analysis of recombination in Saccharomyces. Mutat. Res. 451, 53–69 (2000).
Helleday, T. Pathways for mitotic homologous recombination in mammalian cells. Mutat. Res. 532, 103–115 (2003).
West, S. C. Molecular views of recombination proteins and their control. Nature Rev. Mol. Cell Biol. 4, 435–445 (2003).
Szostak, J. W., Orr-Weaver, T. L., Rothstein, R. J. & Stahl, F. W. The double-strand-break repair model for recombination. Cell 33, 25–35 (1983).
Baehner, F. L. et al. Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories. J. Clin. Oncol. 28, 4300–4306 (2010).
McClintock, B. The production of homozygous deficient tissues with mutant characteristics by means of the aberrant mitotic behavior of ring-shaped chromosomes. Genetics 23, 315–376 (1938).
Ma, C., Martin, S., Trask, B. & Hamlin, J. L. Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes Dev. 7, 605–620 (1993).
Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).
Roberts, S. A. et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46, 424–435 (2012).
Burrell, R. A. et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492–496 (2013).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Spruck, C. H., Won, K. A. & Reed, S. I. Deregulated cyclin E induces chromosome instability. Nature 401, 297–300 (1999).
Zimmerman, K. M., Jones, R. M., Petermann, E. & Jeggo, P. A. Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress. Mol. Cancer Res. 11, 370–380 (2013).
Takeda, D. Y. & Dutta, A. DNA replication and progression through S phase. Oncogene 24, 2827–2843 (2005).
Tsantoulis, P. K. et al. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27, 3256–3264 (2008).
Barlow, J. et al. A novel class of early replicating fragile sites that contribute to genome instability in B cell lymphomas. Cell 152, 620–632 (2013).
Gellert, M. et al. V(D)J recombination: links to transposition and double-strand break repair. Cold Spring Harb. Symp. Quant. Biol. 64, 161–167 (1999).
Neuberger, M. S., Harris, R. S., Di Noia, J. & Petersen-Mahrt, S. K. Immunity through DNA deamination. Trends Biochem. Sci. 28, 305–312 (2003).
Vaandrager, J. W., Schuuring, E., Philippo, K. & Kluin, P. M. V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma. Blood 96, 1947–1952 (2000).
Robbiani, D. F. et al. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135, 1028–1038 (2008).
Ramiro, A. R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431–438 (2004).
Berry, M. W., Browne, M., Langville, A. N., Pauca, V. P. & Plemmons, R. J. Algorithms and applications for approximate nonnegative matrix factorization. Comput. Statist. Data Analysis 52, 155–173 (2007).
Lange, S. S., Takata, K. & Wood, R. D. DNA polymerases and cancer. Nature Rev. Cancer 11, 96–110 (2011).
The authors thank the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Swedish Cancer Society, the Swedish Pain Relief Foundation and the Torsten and Ragnar Söderberg Foundation (all to T.H.). S.N-Z. is personally funded through a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome-Beit Prize Fellow.
The authors declare no competing financial interests.
- Driver mutations
Genetic changes that give selective advantages to clones during cancer development.
- Somatic mutations
Mutations that are acquired as opposed to inherited.
- Passenger mutations
Genetic changes that do not confer any selective advantage in cancer development.
- Mutational processes
Biological activities that generate mutations; each of these processes comprises both a DNA damage component and a DNA repair component. These processes can be ongoing or historical depending on whether the biological processes that cause the acquisition of mutations in a cancer are active or inactive, respectively.
- Mutational signature
The pattern of mutations produced by a mutational process.
- Mutational portrait
The total genetic changes observed in a cancer genome; that is, the sum of all mutational signatures occurring in a lifetime.
- Base substitutions
A type of mutation in which one base is replaced by another in DNA.
- Insertions and deletions
(Indels). A type of mutation that arises from the insertion or deletion of one or more nucleotides within a DNA sequence.
- Structural variations
Large-scale genomic changes (typically >1 kb) such as deletions, tandem duplications, amplifications, inversions and translocations.
Mutations that involve different classes of nucleotides; that is, purine-to-pyrimidine or pyrimidine-to-purine mutations.
Mutations that involve the same class of nucleotides; that is, purine-to-purine or pyrimidine-to-pyrimidine mutations.
A biochemical reaction that removes an amine group from a molecule.
- Transcriptional strand bias
Bias in mutation load between the transcribed strand and the non-transcribed strand.
- Microsatellite instability
Variability in the length of base pair repeated sequences (<5 bp) that is caused by replication slippage and that is normally kept stable by mismatch repair.
- Replication fork collapse
A condition at a replication fork in which the integrity of a DNA molecule is impaired and can result in a DNA double-strand break.
- Somatic hypermutation
Regional hypermutation at the immunoglobulin locus that generates antibody diversity.
- Synthesis-dependent end-joining
(SDEJ). A process in which a DNA end at a double-strand break is extended using the intact sister chromatid as template. The DNA end is released from the sister chromatid and rejoined by end-joining.
An event with tens or hundreds of locally clustered rearrangements that result in distinct oscillations of copy-number states.
A rearrangement event that involves multiple chromosomes.
A base substitution hypermutation that comprises C·G→T·A transitions and C·G→G·C transversions with a predilection for a thymine preceding the mutated cytosine (that is, a TpC context); it usually macroscopically colocalizes with structural variation.
- Chromosomal instability
A process that results in failure to maintain euploidy after mitosis and that is caused by either numerical or structural chromosomal aberrations.
- Replication stress
A condition in which progression of a replication fork is hindered.
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Helleday, T., Eshtad, S. & Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet 15, 585–598 (2014). https://doi.org/10.1038/nrg3729
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