Key Points
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Increased spontaneous or environmentally enhanced mutagenesis often correlates with increased mutation load and cancer risk. Mutation loads of individual cancer genomes can differ by several orders of magnitude and the top mutation loads are defined as having a hypermutation phenotype.
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Recent accumulation of cancer genomics information caused a breakthrough in understanding the origin and mechanisms of hypermutation. Mutation rates and distribution across cancer genomes are influenced by features of genome structure and function, such as replication timing, transcription and chromatin structure. Mutation rates also increase in the vicinity of rearrangement breakpoints
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Mutation rates can vary depending on local DNA sequence and the kind of genetic change. These parameters are defined as mutation signatures. Statistical analysis of somatic mutation signatures in cancer genomes has deciphered new sources of hypermutation in cancer and has confirmed the role of classic carcinogenic mutagens in cancer hypermutation.
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Mutation signatures can be identified by large-scale statistical analysis (termed non-negative matrix factorization (NMF)) of complex genome-wide mutation catalogues, as well as through selecting a fraction of mutations enriched with a single mutagenic mechanism. The latter can be achieved by concentrating on groups of closely spaced mutations: that is, mutation clusters.
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Combining NMF methods with analyses that concentrate on clustered mutations helped to identify a new kind of strong and ubiquitous carcinogenic mutagen that acts endogenously — a subclass of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases. The use of these complementary techniques greatly enhanced the statistical power to analyse APOBEC-mediated mutagenesis in cancer.
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Merging statistical pattern analysis with mechanistic information is feasible for other sources of mutations for which vast mechanistic knowledge has been accumulated over past decades. This can lead to the identification of new environmental, occupational and endogenous sources of hypermutation, as well as to an understanding of their specific affects in different cancer types, and even in individual cancer samples.
Abstract
A role for somatic mutations in carcinogenesis is well accepted, but the degree to which mutation rates influence cancer initiation and development is under continuous debate. Recently accumulated genomic data have revealed that thousands of tumour samples are riddled by hypermutation, broadening support for the idea that many cancers acquire a mutator phenotype. This major expansion of cancer mutation data sets has provided unprecedented statistical power for the analysis of mutation spectra, which has confirmed several classical sources of mutation in cancer, highlighted new prominent mutation sources (such as apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) enzymes) and empowered the search for cancer drivers. The confluence of cancer mutation genomics and mechanistic insight provides great promise for understanding the basic development of cancer through mutations.
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Change history
28 September 2015
In the version of this article that was originally published, there were errors in parts of the text referring to the temozolomide-associated mutation signature. In Table 2, the resulting base should be a T and the resulting base change should be C→T. In Box 1, example 3 should compare the overlapping mutation signatures of tobacco and DNA polymerase ε, not those of tobacco and temozolomide. These errors have now been corrected online.
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Acknowledgements
The authors are grateful to D. Kwiatkowski, D. Zaykin and K. Chan for advice on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (D.A.G. and S.A.R.) and by an NIH Pathway to Independence Award K99ES022633-01 (S.A.R.)
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Glossary
- Mutation load
-
The number of mutations in the genome or part of the genome of a cell, a group of cells (tumour, tissue and so on) or an organism.
- Mutation rates
-
(Also known as mutation frequencies). The numbers of mutations per unit of length (for example, per Megabase) or biological time (for example, per cell generation).
- Drivers
-
Mutations that increase the probability of tumour incidence.
- Structural rearrangements
-
Changes in the location of genomic regions relative to each other.
- Mutation reporters
-
DNA sequences that, when mutated in a cell, give the cell a phenotype that can be selected. In most cases the mutation either restores the function of an inactive protein or provides resistance to a drug.
- Mutation spectrum
-
The list of mutation types and coordinates within a mutation load.
- Late replicating regions
-
Regions of the genome where DNA is synthesized near the end of S-phase during replication.
- Transcription-coupled repair
-
(TCR). A form of nucleotide excision repair that utilizes a stalled RNA polymerase as a means to recognize a DNA lesion in the transcribed strand.
- Nucleotide excision repair
-
(NER). A DNA repair pathway that removes bulky DNA lesions by removing a stretch of the DNA strand containing the lesion and then by subsequently using the remaining undamaged DNA strand as a template to synthesize a new stretch of DNA to replace the excised one.
- Mutation signatures
-
Characteristics of a mutation, such as the mutated base, the resulting base (or bases) and nucleotides in the immediate vicinity that occur more frequently than expected with random mutation of genomic DNA.
- DNA lesion
-
A specific change in DNA structure that results from DNA damage; for example, cytidine deamination, base alkylation, base oxidation, strand crosslinks, ultraviolet-induced dimers and DNA breakage.
- Mutation clusters
-
Groups of mutations that are spaced more closely than expected by random distribution of mutations in a genome.
- Break-induced replication
-
A DNA double-strand-break repair mechanism involving the invasion of one DNA end into a homologous locus on a sister chromatid or homologous chromosome. Once invaded, the broken DNA is used to prime replication to the end of the unbroken sister chromatid or homologous chromosome to replace the DNA sequence that is lost owing to the DNA double-strand-break.
- Translesion synthesis
-
(TLS). A form of lesion tolerance that involves the insertion of a new nucleotide opposite a DNA lesion, usually by a specialized DNA polymerase.
- R-loops
-
Stable hybrids of RNA and DNA that are formed during transcription.
- Strand-coordination
-
A phenomenon in which clustered mutations involve changes of only one kind of base within the same DNA strand (for example, C-coordination — only cytosines are mutated in the top DNA strand)
- Non-canonical excision repair
-
Excision of a DNA lesion or modification that does not completely follow the pathway mechanisms of base excision repair, nucleotide excision repair or mismatch repair.
- Kataegis
-
(or mutation shower). A group of clustered mutations carrying additional similarity features that are unlikely to be random (for example, changes of the same nucleotide in the given strand — strand-coordination).
- Rearrangement breakpoints
-
A pair of distant genomic coordinates that are brought into the immediate vicinity of each other by a rearrangement.
- SN1-type alkylating agents
-
Chemicals that form a reactive intermediate in the body that can attack DNA bases to covalently link an organic group (for example, a methyl group).
- Mismatch repair
-
(MMR). A DNA repair pathway that removes mismatched nucleotides resulting from DNA replication errors (for example, C·T base pairs). MMR removes a stretch of the DNA strand containing the mismatched nucleotide and then subsequently uses the remaining intact DNA strand as a template to synthesize a new stretch of DNA to replace the excised one.
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Roberts, S., Gordenin, D. Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 14, 786–800 (2014). https://doi.org/10.1038/nrc3816
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DOI: https://doi.org/10.1038/nrc3816
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