{"entity":{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","aka":[],"tldr":"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.","summary":"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).","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Knudson_hypothesis","links":[{"label":"Vogelstein et al., Cancer genome landscapes (Science 2013)","url":"https://doi.org/10.1126/science.1235122"},{"label":"Kinzler & Vogelstein, Gatekeepers and caretakers (Nature 1997)","url":"https://doi.org/10.1038/386761a0"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["retinoblastoma","colorectal","cml"],"sections":[],"technologies":["cgp","germline-testing","kinase-inhibitors","synthetic-lethality-approaches","crispr-screens"],"targets":["kras","braf","her2","egfr","alk","tp53","brca","prmt5-mtap","ewsr1-fli1","bcr-abl"],"drugs":["imatinib","osimertinib","sotorasib","trastuzumab","olaparib"],"companies":[],"institutions":[],"pathways":["ras-mapk","p53-cell-cycle","clonal-evolution","mutagenesis-signatures"],"terms":["oncogene-addiction","gene-fusion","hereditary-cancer-syndromes","germline-vs-somatic","synthetic-lethality","vus"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kinzler-nature"],"journals":[],"dependsOn":[],"notes":[],"analogy":"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.","nodes":[{"id":"proto","label":"Proto-oncogene","x":15,"y":15},{"id":"act","label":"Mutation, amp, fusion","x":15,"y":45,"targetId":"kras"},{"id":"onc","label":"Oncogene ON (1 hit)","x":15,"y":78},{"id":"ts","label":"Tumour suppressor","x":55,"y":15,"targetId":"tp53"},{"id":"hit1","label":"1st hit (germline/somatic)","x":55,"y":45},{"id":"hit2","label":"2nd hit: LOH, methylation","x":85,"y":45},{"id":"loss","label":"Brake lost (2 hits)","x":55,"y":78},{"id":"pass","label":"Passengers, neoantigens","x":85,"y":15},{"id":"growth","label":"Clonal expansion","x":55,"y":96}],"edges":[{"from":"proto","to":"act","type":"activates"},{"from":"act","to":"onc","type":"activates"},{"from":"onc","to":"growth","type":"activates"},{"from":"ts","to":"growth","type":"inhibits"},{"from":"hit1","to":"ts","type":"inhibits"},{"from":"hit2","to":"ts","type":"inhibits"},{"from":"hit1","to":"loss","type":"activates"},{"from":"hit2","to":"loss","type":"activates"},{"from":"loss","to":"growth","type":"activates"},{"from":"pass","to":"growth","type":"activates"}],"interventions":["Oncogene addiction is the basis of every targeted kinase inhibitor and of HER2 antibodies","Suppressor loss cannot be 'inhibited', so it is exploited indirectly: synthetic lethality (BRCA-PARP, MTAP-PRMT5), CDK4/6 for RB-intact, MDM2 for TP53-wild-type","Germline first hits drive surveillance and risk-reducing surgery in hereditary syndromes","Comprehensive genomic profiling separates drivers from passengers at diagnosis"]},"route":"/pathways/oncogene-activation-two-hit/","neighbours":{"cancer":[{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"multiple-endocrine-neoplasia","kind":"cancer","name":"Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)","route":"/cancers/multiple-endocrine-neoplasia/"},{"id":"retinoblastoma","kind":"cancer","name":"Retinoblastoma","route":"/cancers/retinoblastoma/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"bcr-abl","kind":"target","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/targets/bcr-abl/"},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"ewsr1-fli1","kind":"target","name":"EWSR1-FLI1 fusion","route":"/targets/ewsr1-fli1/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"nf1","kind":"target","name":"NF1 (neurofibromin)","route":"/targets/nf1/"},{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","route":"/targets/prmt5-mtap/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"term":[{"id":"driver-passenger-model","kind":"term","name":"Driver and passenger mutations: the refined somatic mutation theory","route":"/terms/driver-passenger-model/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/"},{"id":"somatic-mutation-theory","kind":"term","name":"Somatic mutation theory of cancer","route":"/terms/somatic-mutation-theory/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"},{"id":"vus","kind":"term","name":"Variant of uncertain significance (VUS)","route":"/terms/vus/"}],"paper":[{"id":"paper-kinzler-nature","kind":"paper","name":"Cancer-susceptibility genes. Gatekeepers and caretakers","route":"/key-papers/paper-kinzler-nature/"}]}}