The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the 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 the evolutionary timing that 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 inter-tumoral 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.

中文翻译：

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胰腺癌的进化森林


胰腺导管腺癌 （PDAC） 的基因组特征已经得到了很好的描述，但这些特征出现的进化背景仍未得到探索。我们研究了 91 例 PDAC 的基因组景观、系统发育和克隆组成与临床病理特征相关的情况。驱动突变的数量或每个突变发生的进化时间没有差异。高躯干密度是导致每个 PDAC 的谱系中体细胞突变积累的指标，与较差的总生存期显著相关。在整个队列中确定了多克隆、单克隆或混合多克隆/单克隆转移，突出了多种形式的肿瘤间异质性。晚期和治疗过的 PDAC 具有较高的多克隆几率，而寡转移性 PDAC 具有较少的驱动改变、较低的等位基因分数丢失和单克隆的可能性增加。总之，我们的研究结果揭示了超越既定遗传范式的 PDAC 基因组动态性质的新见解。