Mechanisms Underlying Mutational Signatures in Human Cancer


The somatic mutations in a cancer cell's genome are the outcome of a collection of mutational processes which have operated at various intensities, continuously or intermittently, during the patient's lifetime. Such processes include DNA damage by endogenous and exogenous agents, as well as errors and defects in DNA replication and repair systems. Each mutational process gives rise to one or more distinctive patterns of mutations, known as mutational signatures. These patterns reflect both the mechanisms whereby damage is inflicted on DNA and the repair or replication mechanisms that interact with this damage. Over the last decade, computational analyses of thousands of cancer genomes have led to the construction and refinement of comprehensive catalogues of mutational signatures. By opening a window into the inner biology of individual tumours, mutational signatures have transformed our understanding of carcinogenesis, and have provided the basis for new approaches to clinical assessment and treatment of cancers.

Key Concepts

  • The somatic mutations in a cancer genome are the product of a collection of mutational processes which have operated on the organism's cells since the moment of fertilisation.
  • The mechanisms of mutation identified in human cancers include DNA damage by endogenous processes and exogenous mutagens, as well as errors and defects in DNA repair and replication processes.
  • A mutational signature represents a characteristic pattern of mutations that is imprinted on the genome by a particular mutational process.
  • Catalogues of consensus mutational signatures, compiled through the analysis of thousands of cancer genomes, can be exploited to determine the mutational processes that are (or have been) active in a particular tumour.
  • The study of mutational signatures can yield insights into the aetiology of individual tumours, informing about the mechanisms that have actively caused damage to DNA, or prevented the repair of this damage; such mechanisms may include preventable carcinogenic exposures, as well as disruption of potentially targetable cellular processes.

Keywords: cancer; somatic mutation; mutagenesis; mutational signatures; mutational processes

Figure 1. Mutation accumulation and neoplastic progression. Diagram illustrating the accumulation of somatic mutations throughout the lineage of mitotic cell divisions connecting the zygote to a late‐stage cancer cell. Coloured bars represent exposure to various types of mutational processes over time (left to right), with the length and width of each bar indicating the duration and intensity of the corresponding exposure. Stars denote mutations acquired by somatic cells, coloured according to the causative mutational process. Cell background colours represent the progression from normal (blue) to progressively disordered (orange) cell phenotypes. After Stratton MR, Campbell PJ, Futreal PA () The cancer genome. Nature 458(7239): 10 719–724.
Figure 2. Graphical representation of an SBS mutational spectrum. Bars present the number of mutations (or, alternatively, the mutation probability) for each of the 96 categories of single base substitutions in a trinucleotide sequence context (horizontal axis). Bars are grouped and coloured according to base substitution type (indicated above each group of bars).
Figure 3. COSMIC SBS signatures with known or proposed aetiologies. Mutational signatures are represented in the same manner as the spectrum in Figure , with bars presenting mutation probabilities. Signature names and associated mutational process types are displayed in the top‐right corner of each spectrum. Mutational signatures were retrieved in numerical form from


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Further Reading

Alexandrov LB and Stratton MR (2014) Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Current Opinion in Genetics & Development 24: 52–60.

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Baez‐Ortega, Adrian(Oct 2020) Mechanisms Underlying Mutational Signatures in Human Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026931]