Mutagenesis & mutational signatures
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.
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.
In one picture
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.
Diagram
top- 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
Pages like this
not linked directly; found by shared links- PathwaySynthetic lethality: paired dependencies
Shares HRD & BRCA testing, Homologous recombination deficiency (HRD), DNA damage response & homologous recombination, Mismatch repair & microsatellite instability and the tags mechanism, mechanics-atlas.
- PathwayBase excision repair, PARP & alkylation damage
Shares MGMT promoter methylation, Temozolomide, Homologous recombination deficiency (HRD), DNA damage response & homologous recombination and the tags mechanism, mechanics-atlas.
- PathwayThe cancer-immunity cycle
Shares Neoantigen, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
- PathwayThe blood–brain barrier & brain metastasis
Shares MGMT promoter methylation, Temozolomide and the tags mechanism, mechanics-atlas.
- PathwayOncogenic viruses
Shares HPV & HBV vaccination, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
- PathwayNutrient competition & metabolic immunosuppression
Shares PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
- PathwayCold tumours: immune deserts and exclusion
Shares Tumour mutational burden (TMB), PD-1 and the tags mechanism, mechanics-atlas.
- PathwayT-cell exhaustion
Shares PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.