# Mutagenesis & mutational signatures

Source: https://onco.cc/pathways/mutagenesis-signatures/  
OnCo record `mutagenesis-signatures` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Every cause of DNA damage leaves its own fingerprint in the genome: sunlight, tobacco, a faulty repair enzyme, a gut bacterium. Reading these fingerprints tells you what caused a cancer and which repair crews it is missing, which in turn predicts which drugs will work.

## Summary

Mutations arise when damage (exogenous: UV, tobacco polycyclics, aflatoxin, alkylators, platinum; endogenous: deamination, APOBEC3A/B cytidine deaminases, ROS, replication errors, colibactin) meets replication before repair, or when repair itself is defective (MMR loss → SBS6/15/26 and MSI; HRD → SBS3 and indel/rearrangement patterns; POLE exonuclease mutation → ultramutation). COSMIC catalogues >60 single-base substitution signatures, plus doublet, indel and copy-number signatures. Clock-like SBS1/SBS5 accumulate with age; APOBEC (SBS2/13) is episodic and therapy-associated; SBS31/35 record prior platinum; temozolomide leaves SBS11. Signatures are now clinical: HRD scores (SBS3, LOH, TAI, LST) select PARP inhibitors; MSI and TMB select immunotherapy; APOBEC activity predicts resistance evolution.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: Footprints in snow. A fox, a dog and a child each leave a distinct print; you can tell who crossed the garden without having seen them. Cancer genomes are snowfields, and each mutagen and each broken repair crew leaves its own print.
- Interventions: Prevention removes the mutagen: smoking cessation, UV protection, HPV/HBV vaccination, aflatoxin control; HRD signatures select PARP inhibitors and platinum; MSI/TMB select checkpoint inhibitors; Signature-aware design: avoid TMZ in MGMT-unmethylated tumours, expect APOBEC-driven resistance; Whole-genome sequencing and methylation profiling read the fingerprints

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Mutational_signatures
- Alexandrov et al., The repertoire of mutational signatures in human cancer (Nature 2020): https://doi.org/10.1038/s41586-020-1943-3
- COSMIC mutational signatures: https://cancer.sanger.ac.uk/signatures/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/), [Vascular tumours (angiosarcoma, epithelioid haemangioendothelioma, kaposiform haemangioendothelioma)](https://onco.cc/cancers/vascular-tumours/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [HPV & HBV vaccination](https://onco.cc/technologies/hpv-vaccine/), [HRD & BRCA testing](https://onco.cc/technologies/hrd-testing/), [Smoking cessation in cancer patients](https://onco.cc/technologies/smoking-cessation-after-diagnosis/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [PARP](https://onco.cc/targets/parp/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Olaparib](https://onco.cc/drugs/olaparib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Temozolomide](https://onco.cc/drugs/temozolomide/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/)
- terms: [Ageing tissue and clonal fields: cancer as a disease of old tissue](https://onco.cc/terms/ageing-tissue-field-theory/), [Driver and passenger mutations: the refined somatic mutation theory](https://onco.cc/terms/driver-passenger-model/), [Enabling characteristic: genome instability and mutation](https://onco.cc/terms/genome-instability-mutation/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [MGMT promoter methylation](https://onco.cc/terms/mgmt/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Mutational signature](https://onco.cc/terms/mutational-signature/), [Neoantigen](https://onco.cc/terms/neoantigen/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- key papers: [Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017/), [Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas](https://onco.cc/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/), [Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes](https://onco.cc/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/), [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Genomic hallmarks and structural variation in metastatic prostate cancer](https://onco.cc/key-papers/paper-quigley-structural-variation-mcrpc-cell-2018/), [Genomic landscape of lung adenocarcinoma in East Asians](https://onco.cc/key-papers/paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020/), [Mutational signatures associated with tobacco smoking in human cancer](https://onco.cc/key-papers/paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016/), [Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer](https://onco.cc/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/), [The landscape of somatic mutation in normal colorectal epithelial cells](https://onco.cc/key-papers/paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019/), [The repertoire of mutational signatures in human cancer](https://onco.cc/key-papers/paper-alexandrov-nature/), [Whole genomes redefine the mutational landscape of pancreatic cancer](https://onco.cc/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/), [Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study](https://onco.cc/key-papers/paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019/)

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