{"entity":{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","aka":[],"tldr":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Mutational_signatures","links":[{"label":"Alexandrov et al., The repertoire of mutational signatures in human cancer (Nature 2020)","url":"https://doi.org/10.1038/s41586-020-1943-3"},{"label":"COSMIC mutational signatures","url":"https://cancer.sanger.ac.uk/signatures/"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["tnbc"],"sections":[],"technologies":["wes-wgs","hrd-testing","cgp","smoking-cessation-after-diagnosis","hpv-vaccine"],"targets":["brca","parp","pd1"],"drugs":["olaparib","pembrolizumab","dostarlimab","temozolomide"],"companies":[],"institutions":[],"pathways":["ddr","mismatch-repair-msi","homologous-recombination-repair","clonal-evolution"],"terms":["mutational-signature","tmb","msi","hrd","mgmt","neoantigen","genome-instability-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-alexandrov-nature"],"journals":[],"dependsOn":[],"notes":[],"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.","nodes":[{"id":"exo","label":"Exogenous: UV, tobacco","x":12,"y":12},{"id":"endo","label":"Endogenous: APOBEC, ROS","x":40,"y":12},{"id":"rep","label":"Replication errors","x":70,"y":12},{"id":"dmg","label":"DNA lesions","x":40,"y":42},{"id":"repair","label":"Repair: MMR, HR, BER, NER","x":78,"y":42,"targetId":"brca"},{"id":"fix","label":"Fixed mutations","x":40,"y":70},{"id":"sig","label":"Signature (SBS, ID, CN)","x":12,"y":70},{"id":"bio","label":"HRD, MSI, TMB biomarkers","x":78,"y":70},{"id":"drv","label":"Drivers, neoantigens","x":40,"y":94}],"edges":[{"from":"exo","to":"dmg","type":"activates"},{"from":"endo","to":"dmg","type":"activates"},{"from":"rep","to":"dmg","type":"activates"},{"from":"repair","to":"dmg","type":"inhibits"},{"from":"dmg","to":"fix","type":"activates"},{"from":"fix","to":"sig","type":"activates"},{"from":"repair","to":"bio","type":"inhibits"},{"from":"fix","to":"bio","type":"activates"},{"from":"fix","to":"drv","type":"activates"}],"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"]},"route":"/pathways/mutagenesis-signatures/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"},{"id":"vascular-tumours","kind":"cancer","name":"Vascular tumours (angiosarcoma, epithelioid haemangioendothelioma, kaposiform haemangioendothelioma)","route":"/cancers/vascular-tumours/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"hpv-vaccine","kind":"technology","name":"HPV & HBV vaccination","route":"/technologies/hpv-vaccine/"},{"id":"hrd-testing","kind":"technology","name":"HRD & BRCA testing","route":"/technologies/hrd-testing/"},{"id":"smoking-cessation-after-diagnosis","kind":"technology","name":"Smoking cessation in cancer patients","route":"/technologies/smoking-cessation-after-diagnosis/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"term":[{"id":"ageing-tissue-field-theory","kind":"term","name":"Ageing tissue and clonal fields: cancer as a disease of old tissue","route":"/terms/ageing-tissue-field-theory/"},{"id":"driver-passenger-model","kind":"term","name":"Driver and passenger mutations: the refined somatic mutation theory","route":"/terms/driver-passenger-model/"},{"id":"genome-instability-mutation","kind":"term","name":"Enabling characteristic: genome instability and mutation","route":"/terms/genome-instability-mutation/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"mgmt","kind":"term","name":"MGMT promoter methylation","route":"/terms/mgmt/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"somatic-mutation-theory","kind":"term","name":"Somatic mutation theory of cancer","route":"/terms/somatic-mutation-theory/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"paper":[{"id":"paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017","kind":"paper","name":"Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma","route":"/key-papers/paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017/"},{"id":"paper-lee-clonal-history-small-cell-transformation-jco-2017","kind":"paper","name":"Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas","route":"/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/"},{"id":"paper-offin-rb1-tp53-transformation-risk-jto-2019","kind":"paper","name":"Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes","route":"/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/"},{"id":"paper-zhang-lung-cancer-never-smokers-nat-genet-2021","kind":"paper","name":"Genomic and evolutionary classification of lung cancer in never smokers","route":"/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/"},{"id":"paper-quigley-structural-variation-mcrpc-cell-2018","kind":"paper","name":"Genomic hallmarks and structural variation in metastatic prostate cancer","route":"/key-papers/paper-quigley-structural-variation-mcrpc-cell-2018/"},{"id":"paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020","kind":"paper","name":"Genomic landscape of lung adenocarcinoma in East Asians","route":"/key-papers/paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020/"},{"id":"paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016","kind":"paper","name":"Mutational signatures associated with tobacco smoking in human cancer","route":"/key-papers/paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016/"},{"id":"paper-rizvi-mutational-landscape-pd1-science-2015","kind":"paper","name":"Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer","route":"/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/"},{"id":"paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019","kind":"paper","name":"The landscape of somatic mutation in normal colorectal epithelial cells","route":"/key-papers/paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019/"},{"id":"paper-alexandrov-nature","kind":"paper","name":"The repertoire of mutational signatures in human cancer","route":"/key-papers/paper-alexandrov-nature/"},{"id":"paper-waddell-whole-genomes-pancreatic-nature-2015","kind":"paper","name":"Whole genomes redefine the mutational landscape of pancreatic cancer","route":"/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/"},{"id":"paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","kind":"paper","name":"Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study","route":"/key-papers/paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019/"}]}}