Pancreatic cancer biology and genetics from an evolutionary perspective

Abstract

Pancreatic cancer evolves in three stages: initiation, expansion and survival in foreign microenvironments. Factors that contribute to initiation are inherited (germline) mutations, somatic mutations acquired during organ growth and renewal, ageing, chronic inflammation, obesity and smoking. Genetic mutations in KRAS, cyclin-dependent kinase inhibitor 2A (CDKN2A), TP53 and SMAD4 drive clonal expansion by conferring a selective growth advantage on pancreatic cancer cells. Selection pressures and bottlenecks result from extension into new microenvironments of immune cells, stroma, organ-specific cell types and resource gradients that vary spatially and temporally. Metastasis requires dispersal, invasion and colonization of microenvironments distant from the pancreatic primary site. Remaining questions include the order of early cancer-promoting events, the phenotypic importance of late-occurring mutations and the clinical relevance of genetic, microenvironmental and cellular heterogeneity. Evolutionary thinking provides a framework for the biology of pancreatic cancer, revealing how and why this lethal tumour evolves.