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Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride.
Vogelstein's landscape: ~140 driver genes, each tumour carrying 2-8 driver events in ~12 pathways, on a background of tens to thousands of passengers. Oncogene activation is dominant and recurrent at hotspots: point mutation (KRAS G12, BRAF V600E, PIK3CA H1047R), amplification (HER2, MYC, MDM2), fusion (BCR-ABL, ALK, RET, NTRK, EWSR1-FLI1), promoter mutation (TERT) or ecDNA. Tumour suppressor loss follows Knudson's two hits, one inherited in hereditary syndromes (RB1, BRCA1/2, APC, MLH1, TP53), the second by deletion, LOH, mutation or methylation; some are haploinsufficient (PTEN). Gatekeepers (APC, RB1) control proliferation directly; caretakers (BRCA, MMR) guard the genome so their loss accelerates all other hits. Oncogene addiction, the dependence of a tumour on its driver, is why kinase inhibitors work; passenger load creates neoantigens and, occasionally, collateral vulnerabilities (MTAP deletion next to CDKN2A → PRMT5 dependence).
A car with a stuck accelerator (oncogene: one fault is enough) and cut brake lines (tumour suppressor: both lines must fail because they are duplicated). The scratches on the paintwork (passengers) did not cause the crash but they tell you what road it drove on.
Shares PRMT5 (MTAP-deleted cancers), Synthetic lethality, Oncogene addiction, Synthetic lethality approaches and the tags mechanism, mechanics-atlas.
Shares Synthetic lethality approaches, Germline vs somatic mutations, p53 / RB / cell-cycle checkpoint, Germline (hereditary) testing and the tags mechanism, mechanics-atlas.
Shares BCR::ABL1 (Philadelphia chromosome), Sotorasib, Clonal evolution & minimal residual disease, ALK and the tags mechanism, mechanics-atlas.
Shares Synthetic lethality, Mutagenesis & mutational signatures, Synthetic lethality approaches, Hereditary cancer syndromes and the tags mechanism, mechanics-atlas.
Shares Clonal evolution & minimal residual disease, Osimertinib, BRAF, EGFR and the tags mechanism, mechanics-atlas.
Shares Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), Oncogene addiction, Gene fusion, ALK and the tags mechanism, mechanics-atlas.
Shares Theories of cancer: how the ideas connect, ALK, HER2, Colorectal cancer and the tags mechanism, mechanics-atlas.
Shares ALK, Osimertinib, EGFR, HER2 and the tags mechanism, mechanics-atlas.