{"entity":{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","aka":[],"tldr":"Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit.","summary":"Chromosomal instability (CIN) arises from mitotic errors, whole-genome doubling, replication stress, and centrosome amplification; it produces aneuploidy, micronuclei, chromothripsis, and ecDNA (extrachromosomal oncogene amplicons). Consequences: intratumour heterogeneity and rapid adaptation (TRACERx), cytosolic DNA that activates cGAS-STING (immunogenic in bursts, tolerated chronically via non-canonical NF-κB), and proteotoxic and metabolic stress that creates dependencies (KIF18A, spindle assembly checkpoint, BCL-XL). CIN is a poor-prognosis marker across cancers; ecDNA drives resistance to targeted therapy in glioblastoma and others.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Chromosome_instability","links":[{"label":"Bakhoum et al., Chromosomal instability drives metastasis through a cytosolic DNA response (Nature 2018)","url":"https://doi.org/10.1038/nature25432"},{"label":"Cancer Grand Challenges eDyNAmiC team","url":"https://cancergrandchallenges.org/teams/edynamic"}],"tags":["mechanism"],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["wes-wgs","single-cell-spatial"],"targets":["tp53","egfr"],"drugs":[],"companies":[],"institutions":["francis-crick","mskcc","stanford","cruk"],"pathways":["cgas-sting","p53-cell-cycle","replication-stress","clonal-evolution"],"terms":["genome-instability-mutation","whole-genome-doubling","mutational-signature"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bakhoum-nature"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Swanton (Crick/UCL, TRACERx, CIN and immune evasion); Bakhoum (MSK, CIN-STING); Mischel (Stanford) and the eDyNAmiC Cancer Grand Challenge on ecDNA; Sheltzer (Yale) on aneuploidy dependencies."],"analogy":"Chromosomal instability is a library that reshuffles and duplicates random shelves every night. Most rearrangements are useless, some ruin the building, but occasionally one yields a book the librarian needs to survive a new rule, and the mess itself keeps the fire alarms twitching.","nodes":[{"id":"mitosis","label":"Mitotic errors, WGD","x":15,"y":25},{"id":"cin","label":"Chromosomal instability","x":45,"y":25},{"id":"aneu","label":"Aneuploidy / karyotype heterogeneity","x":75,"y":25},{"id":"micro","label":"Micronuclei → cytosolic DNA","x":30,"y":60},{"id":"sting","label":"cGAS-STING","x":30,"y":90},{"id":"ecdna","label":"ecDNA oncogene amplification","x":75,"y":60,"targetId":"egfr"},{"id":"evol","label":"Clonal evolution, resistance","x":92,"y":45},{"id":"dep","label":"Dependencies: KIF18A, SAC, BCL-XL","x":60,"y":90},{"id":"p53","label":"TP53 loss permits","x":15,"y":60,"targetId":"tp53"}],"edges":[{"from":"mitosis","to":"cin","type":"activates"},{"from":"cin","to":"aneu","type":"activates"},{"from":"aneu","to":"evol","type":"activates"},{"from":"cin","to":"micro","type":"activates"},{"from":"micro","to":"sting","type":"activates"},{"from":"cin","to":"ecdna","type":"activates"},{"from":"ecdna","to":"evol","type":"activates"},{"from":"aneu","to":"dep","type":"activates"},{"from":"p53","to":"cin","type":"activates"}],"interventions":["KIF18A inhibitors (sovilnesib) selectively kill CIN-high cells; phase 1/2 in ovarian and TNBC","ecDNA-directed strategies (CHK1 inhibition, transcription-replication conflict) from the Cancer Grand Challenges eDyNAmiC team","STING pathway modulation; radiation exploits CIN","Aneuploidy scores (TRACERx) as prognostic biomarkers"]},"route":"/pathways/chromosomal-instability/","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":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"cruk","kind":"institution","name":"Cancer Research UK","route":"/institutions/cruk/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"pathway":[{"id":"cgas-sting","kind":"pathway","name":"cGAS-STING innate sensing","route":"/pathways/cgas-sting/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"mitotic-spindle-checkpoint","kind":"pathway","name":"Mitosis & the spindle assembly checkpoint","route":"/pathways/mitotic-spindle-checkpoint/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"term":[{"id":"aneuploidy-theory-of-cancer","kind":"term","name":"Aneuploidy and chromosomal instability as the cause of cancer","route":"/terms/aneuploidy-theory-of-cancer/"},{"id":"genome-instability-mutation","kind":"term","name":"Enabling characteristic: genome instability and mutation","route":"/terms/genome-instability-mutation/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"paper":[{"id":"paper-fearon-cell","kind":"paper","name":"A genetic model for colorectal tumorigenesis","route":"/key-papers/paper-fearon-cell/"},{"id":"paper-notta-punctuated-evolution-pancreatic-nature-2016","kind":"paper","name":"A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns","route":"/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/"},{"id":"paper-bakhoum-nature","kind":"paper","name":"Chromosomal instability drives metastasis through a cytosolic DNA response","route":"/key-papers/paper-bakhoum-nature/"},{"id":"paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016","kind":"paper","name":"Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers","route":"/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/"},{"id":"paper-tcga-lung-squamous-nature-2012","kind":"paper","name":"Comprehensive genomic characterization of squamous cell lung cancers","route":"/key-papers/paper-tcga-lung-squamous-nature-2012/"},{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung 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