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Mechanisms underlying mutational signatures in human cancers

Nature Reviews Genetics volume 15, pages 585–598 (2014)Cite this article

Subjects

Key Points

  • 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.

Abstract

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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Figure 1: Active mutational processes over the course of cancer development.
Figure 2: Summary of known mutational signatures, and the components of DNA damage and repair that constitute the mutational processes.
Figure 3: DNA repair pathways and mutational consequences.
Figure 4: Bypass of replication forks blocked by lesions.
Figure 5: Gene rearrangements in cancer.

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Acknowledgements

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.

Author information

Authors and Affiliations

  1. Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, Stockholm, S-171 21, Sweden

    Thomas Helleday & Saeed Eshtad

  2. Wellcome Trust Sanger Institute, Hinxton Genome Campus, Cambridge, CB10 1SA, UK

    Serena Nik-Zainal

  3. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, CB2 2QQ, UK

    Serena Nik-Zainal

Authors
  1. Thomas Helleday
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  2. Saeed Eshtad
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  3. Serena Nik-Zainal
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Corresponding authors

Correspondence to Thomas Helleday or Serena Nik-Zainal.

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Competing interests

The authors declare no competing financial interests.

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Glossary

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.

Transversions

Mutations that involve different classes of nucleotides; that is, purine-to-pyrimidine or pyrimidine-to-purine mutations.

Transitions

Mutations that involve the same class of nucleotides; that is, purine-to-purine or pyrimidine-to-pyrimidine mutations.

Deamination

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.

Chromothripsis

An event with tens or hundreds of locally clustered rearrangements that result in distinct oscillations of copy-number states.

Chromoplexy

A rearrangement event that involves multiple chromosomes.

Kataegis

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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