# A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

Source: https://onco.cc/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/  
OnCo record `paper-notta-punctuated-evolution-pancreatic-nature-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2016
- DOI: 10.1038/nature19823
- Authors: Notta F, Chan-Seng-Yue M, Lemire M, et al.
- Findings: Two-thirds of tumours show complex rearrangements from mitotic errors.; Canonical drivers can be knocked out simultaneously rather than in sequence.
- What it means: 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.

## Sources

- Notta et al., Nature 2016: a renewed, punctuated model of pancreatic cancer evolution: https://doi.org/10.1038/nature19823
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27732578/

## Connected records

- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [CDKN2A](https://onco.cc/targets/cdkn2a/), [KRAS](https://onco.cc/targets/kras/), [SMAD4](https://onco.cc/targets/smad4/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Ontario Institute for Cancer Research](https://onco.cc/institutions/oicr/), [Princess Margaret Cancer Centre](https://onco.cc/institutions/princess-margaret/)
- pathways: [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/)
- terms: [KRAS allelic imbalance and mutant KRAS dosage in pancreatic cancer](https://onco.cc/terms/kras-allelic-imbalance/), [Whole-genome doubling (WGD)](https://onco.cc/terms/whole-genome-doubling/)
- journals: [Nature](https://onco.cc/journals/nature/)

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