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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.
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.
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.
Shares KRAS allelic imbalance and mutant KRAS dosage in pancreatic cancer, Whole-genome doubling (WGD), Ontario Institute for Cancer Research, Chromosomal instability & aneuploidy.
Shares SMAD4, CDKN2A, Nature, Whole-exome & whole-genome sequencing.
Shares SMAD4, Clonal evolution & minimal residual disease, TP53, KRAS.
Shares SMAD4, Clonal evolution & minimal residual disease, TP53, KRAS.
Shares Ontario Institute for Cancer Research, Princess Margaret Cancer Centre, Whole-exome & whole-genome sequencing, Pancreatic ductal adenocarcinoma.
Shares Clonal evolution & minimal residual disease, Nature, Whole-exome & whole-genome sequencing, Pancreatic ductal adenocarcinoma.