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
