Clonal Evolution

Mutational Signature

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Mutational Signature

Definition

A mutational signature is a characteristic pattern of somatic mutations — defined by the relative frequencies of different substitution types in their trinucleotide sequence context — that reflects the activity of a specific DNA damage or repair process during a cell’s evolutionary history. Mutational signatures are extracted from the full catalog of somatic mutations in a cancer genome using mathematical decomposition methods such as non-negative matrix factorization (Nik-Zainal et al., 2012).

Rationale

The key insight is that passenger-mutations, which constitute the vast majority of somatic mutations in a cancer, preserve an unbiased record of the mutational processes that have been active throughout the tumor’s lifetime. As Nik-Zainal et al. (2012) explain: “These bystanders bear the imprints of the DNA damage and repair processes operative during the development of the cancer, unmodified by selection” (p. 980). Historically, mutation pattern analysis was restricted to cancer genes like TP53, where selective effects confound the mutational signal. Whole-genome sequencing of passengers bypasses this limitation.

Extraction Method

Non-negative matrix factorization (NMF) decomposes the matrix of mutation counts (96 substitution types × samples) into a set of mutational signatures, each defined by its characteristic profile across the 96 trinucleotide contexts, and a matrix of exposure estimates reflecting the activity of each signature in each sample (Nik-Zainal et al., 2012).

Key Signatures Identified

Nik-Zainal et al. (2012) demonstrated the approach in 21 breast cancers, identifying signatures including:

  • Signature 1A/B: C>T transitions at NpCpG dinucleotides — associated with age-related spontaneous deamination of 5-methylcytosine
  • Signature 3: Characteristic of BRCA1/2-deficient cancers — associated with defective homologous recombination repair
  • Signatures 2 and 13: C>T and C>G mutations at TpC dinucleotides — attributed to APOBEC-mutagenesis
  • The study also discovered kataegis — localized clusters of hypermutation colocalizing with rearrangement breakpoints

Temporal Dynamics

Gerstung et al. (2020) demonstrated that the mutational spectrum changes significantly throughout tumor evolution in approximately 40% of samples. Some signatures are more active early (clonal), others late (subclonal), implying changing exposures or repair deficiencies over the tumor’s lifetime. This finding means that a single tumor sample provides only a time-averaged view of the mutational processes that have shaped it.

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