Mutational Signatures: Reading a Tumour's History
Different mutational processes leave different fingerprints on the genome. A mutational signature is the characteristic distribution of base changes and their sequence context produced by one process, such as ultraviolet light, tobacco smoke, APOBEC enzymes or a specific repair defect. Decomposing a tumour's mutations into signatures can suggest what has shaped it.
Quick Answer
Different mutational processes leave different fingerprints on the genome. A mutational signature is the characteristic distribution of base changes and their sequence context produced by one process, such as ultraviolet light, tobacco smoke, APOBEC enzymes or a specific repair defect. Decomposing a tumour's mutations into signatures can suggest what has shaped it.
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DNA Repair and Genomic Instability
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A few of the best-characterised single-base-substitution signatures and what they can indicate. Patterns are simplified; signature labels follow the widely used COSMIC catalogue.
| Process | Pattern in brief | What it can indicate |
|---|---|---|
| Ultraviolet light | C>T at adjacent pyrimidines | Sun-exposure mutagenesis (melanoma, skin) |
| Tobacco smoke | C>A transversions | Smoking-related mutagenesis (lung, head and neck) |
| APOBEC | Clustered C>T and C>G at TpC | Endogenous cytidine-deaminase activity |
| Mismatch-repair deficiency | Indels at repeats, specific base changes | MSI-high, Lynch-syndrome context |
| Homologous recombination deficiency | Deletions at microhomology, rearrangements | Possible platinum and PARP-inhibitor sensitivity |
| POLE proofreading loss | C>A and C>T in specific trinucleotides | Ultramutated tumour |
How a Signature Is Defined
The most established framework classifies each single-base substitution by the change (for example C>T) and the flanking bases, giving 96 categories. Large pan-cancer datasets were factorised mathematically into a set of reference signatures, each a probability distribution over those 96 categories.
Additional catalogues exist for small insertions and deletions and for structural rearrangements. Some reference signatures have a known cause; others remain of unknown aetiology.
What Signatures Can Suggest
A dominant UV signature points to sun exposure; a tobacco signature to smoking-related mutagenesis; a signature of many small deletions at microhomology to homologous recombination deficiency; a TpC-context signature to APOBEC activity.
Signatures accumulate over time, so a tumour genome carries a mixture reflecting its whole history, including processes that were active early and are now silent.
Interpretive Limits
Signature fitting is a statistical estimate. Low mutation counts, targeted panels rather than whole genomes, sequencing artefacts and closely related reference signatures all reduce confidence.
A signature associated with a repair defect is supportive evidence, not a functional assay, and should be read alongside the actual variants detected and the clinical context.
From Signature to Action
A minority of signatures currently carry direct clinical weight. The homologous-recombination-deficiency and mismatch-repair signatures can support treatment decisions that are usually made on dedicated assays, and a proofreading or APOBEC signature helps explain an unexpectedly high mutation count. Most other signatures are descriptive.
The practical rule is that a signature reinforces or challenges a result obtained another way. It rarely stands alone as the basis for a therapy, and a weak or panel-derived signature call should be treated cautiously.
Key Takeaways
- ·Mutational signatures are context-specific patterns left by distinct mutational processes.
- ·They can implicate exposures such as UV or tobacco, or defects such as HRD or proofreading loss.
- ·Signature analysis is a probabilistic estimate that depends heavily on assay breadth and mutation count.
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Frequently asked questions
Can a targeted gene panel give reliable mutational signatures?
Usually not. Signature fitting is a statistical estimate that needs many mutations; low counts, panel-only data, sequencing artefacts and similar reference signatures all reduce confidence, and whole-genome or whole-exome data is preferred.
What can a mutational signature actually tell you?
It can implicate a past exposure such as ultraviolet light or tobacco, or a process such as APOBEC activity, homologous recombination deficiency or polymerase-proofreading loss — as supportive evidence, not a functional assay.
Why does one tumour show several signatures?
Signatures accumulate over time, so a tumour genome carries a mixture reflecting its whole history, including processes that were active early and have since stopped.
References
Continue Reading
Tumour Mutational Burden: How TMB Is Measured
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APOBEC Mutagenesis: An Internal Source of Cancer Mutations
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Nucleotide Excision Repair, Xeroderma Pigmentosum and Platinum Response
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POLE and POLD1 Proofreading Mutations: Ultramutated Tumours
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HRD Scores and Genomic Scars: What an HRD-Positive Result Means
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MGMT Promoter Methylation: A Glioma Treatment Biomarker
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