SMAD4 and neoplasm: The subsequent acquisition of mutations in a number of tumour suppressor genes, notably CDKN2A, TP53 and DPC4, and many more at lower frequencies,4 leads to tumour progression and metastasis, in a process now believed to occur over a period of 10–20 years.5 Recent sequencing studies of pancreatic cancer have reinforced the complexity and heterogeneity of this disease.4 Thus, although there may be pathways that are key to driving specific tumours, they may be deregulated relatively rarely.