Pancreatic cancer does not appear all at once. Most pancreatic ductal adenocarcinomas pass through a sequence of microscopic precursor lesions called pancreatic intraepithelial neoplasia (PanIN), in which the lining of the ducts becomes progressively more abnormal before a tumour becomes invasive. PanINs are common in the pancreas of older people, and most do not become cancer, so a precursor is not the same as a tumour; what drives progression is the accumulation of genetic damage.
The first genetic change is usually a mutation in KRAS, an oncogene that forms part of the MAPK signalling pathway, the cascade that tells a cell to divide. A mutated KRAS protein stays switched on, so the cell receives a continuous signal to proliferate. KRAS is mutated in more than 90% of pancreatic ductal adenocarcinomas and is already present in low-grade precursor lesions, which is why it is regarded as the initiating event rather than a late one.
As the lesion advances, damage accumulates in tumour-suppressor genes — the genes whose normal job is to restrain growth — and each loss removes a different brake on the cell:
- CDKN2A encodes the protein p16, which controls entry into the cell cycle; its loss of function lets cells pass a checkpoint that would otherwise stop them dividing.
- TP53 encodes p53, which arrests the cell cycle or triggers cell death when DNA is damaged; its mutation lets damaged cells survive and accumulate further faults.
- SMAD4 carries growth-restraining signals from the TGF-β pathway; its loss is associated with more aggressive, metastatic disease.
Invasive pancreatic cancer is therefore not caused by a single mutation but by the combined effect of an oncogene that cannot be switched off and several tumour suppressors that have been lost, leaving the duct cell unresponsive to the signals that normally control its growth.