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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.
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.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
It shows that the driver frequencies quoted in Western guidelines are population statistics rather than facts about the disease, which matters for how many patients anywhere are expected to benefit from a given medicine.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It gives the sequencing report a prognostic reading that does not depend on a repeat biopsy: an EGFR-mutant cancer that also carries RB1 and TP53 alterations will stop responding sooner and should be watched for a change of histology.
It sets the baseline the adenoma-carcinoma sequence starts from and warns against reading a driver mutation found in tissue, or in stool or blood, as evidence of cancer.
It is the best population-based estimate of how much TNBC is homologous recombination deficient, shows that most of it is not germline BRCA, and argues that whole-genome sequencing at diagnosis could stratify trials and pick out the low group that needs something other than DNA-damaging chemotherapy.
It shows that the commonest driver event in advanced prostate cancer is invisible to the panels used to test for it, and that the shape of the structural damage in a genome tells you which repair pathway failed, which is information a mutation list does not carry.
Signatures find repair-deficient tumours that gene panels miss, and they mark the minority in which checkpoint drugs have a rationale.
Shares HRD & BRCA testing, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining, Mismatch repair & microsatellite instability and the tags mechanism, mechanics-atlas.
Shares MGMT promoter methylation, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD) and the tags mechanism, mechanics-atlas.
Shares Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas, Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes, Clonal evolution & minimal residual disease, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
Shares MGMT promoter methylation, Temozolomide, Non-small-cell lung cancer and the tags mechanism, mechanics-atlas.
Shares Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer, Neoantigen, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
Shares Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas, Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes, Non-small-cell lung cancer and the tags mechanism, mechanics-atlas.
Shares Somatic mutation theory of cancer, HPV & HBV vaccination, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
Shares Tumour mutational burden (TMB), PD-1, Pancreatic ductal adenocarcinoma, Colorectal cancer and the tags mechanism, mechanics-atlas.