{"entity":{"id":"paper-notta-punctuated-evolution-pancreatic-nature-2016","kind":"paper","name":"A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns","aka":[],"tldr":"Tracking chromosome damage in tumour-enriched genomes showed that pancreatic cancer often does not acquire its driver mutations one at a time: in two-thirds of tumours a catastrophic mitotic error knocks out several at once, so the disease can become invasive in a jump.","summary":"Using new informatics tools, changes in DNA copy number and associated rearrangements were tracked in tumour-enriched genomes. The prevailing model predicts a particular sequence (KRAS, then CDKN2A, then TP53 and SMAD4) acquired gradually. Two-thirds of tumours harboured complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory; in a subset the consequence was the simultaneous rather than sequential knockout of canonical preneoplastic drivers, likely setting off invasive growth.","asOf":"2026-09-24","links":[{"label":"Notta et al., Nature 2016: a renewed, punctuated model of pancreatic cancer evolution","url":"https://doi.org/10.1038/nature19823"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27732578/"}],"tags":[],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":["wes-wgs"],"targets":["kras","tp53","cdkn2a","smad4"],"drugs":[],"companies":[],"institutions":["oicr","princess-margaret"],"pathways":["chromosomal-instability","clonal-evolution"],"terms":["whole-genome-doubling"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2016,"doi":"10.1038/nature19823","pmid":"27732578","authors":"Notta F, Chan-Seng-Yue M, Lemire M, et al.","paperType":"translational","findings":["Two-thirds of tumours show complex rearrangements from mitotic errors.","Canonical drivers can be knocked out simultaneously rather than in sequence."],"whatItMeans":"The textbook PanIN-to-cancer ladder is only part of the story, and a screening programme cannot assume years of orderly progression in every patient.","caveats":["Inference from bulk copy-number and rearrangement patterns.","The proportion of cancers arising by each route is uncertain."],"changedPractice":false},"route":"/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/","neighbours":{"cancer":[{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"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":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"oicr","kind":"institution","name":"Ontario Institute for Cancer Research","route":"/institutions/oicr/"},{"id":"princess-margaret","kind":"institution","name":"Princess Margaret Cancer Centre","route":"/institutions/princess-margaret/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"}],"term":[{"id":"kras-allelic-imbalance","kind":"term","name":"KRAS allelic imbalance and mutant KRAS dosage in pancreatic cancer","route":"/terms/kras-allelic-imbalance/"},{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}