The Evolutionary Forest of Pancreatic Cancer

Abstract The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which these features occur remain unexplored. We studied genome landscapes, phylogenies, and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or evolutionary timing when each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal, or mixed polyclonal/monoclonal metastases were identified across the cohort, highlighting multiple forms of intertumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss, and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms. Significance: Although the pancreatic cancer genome has been described, it has not been explored with respect to stages of diagnosis or treatment bottlenecks. We now describe and quantify the genomic features of PDAC in the context of evolutionary metrics and in doing so have identified a novel prognostic biomarker.