Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.

胰腺癌表达谱很大程度上反映了经典或基底样表型。这些特征在患者体内变化的程度是未知的。我们在多区域取样的转移性胰腺癌中整合了进化分析和表达谱，发现鳞状细胞特征是 RNA-seq 定义的基底样亚型的组织学相关性。在同时存在基底和鳞状以及经典和腺体形态的患者中，系统发育研究显示鳞状形态代表其他经典和腺体肿瘤中的亚克隆群。具有鳞状细胞特征的癌症明显更有可能在染色质修饰物中发生克隆突变，MYC的细胞间异质性放大和嵌入。这些数据为在胰腺癌克隆进化的背景下整合染色质修饰基因的基底型表达谱、鳞状组织学和体细胞突变提供了统一的范例。