Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.

胰腺腺癌在患者中表现为一系列高度侵袭性疾病。由于肿瘤细胞性差和广泛的基因组不稳定性，这种疾病异质性的基础已被证明难以解决。为了解决这个问题，从原发性和转移性肿瘤的纯化上皮中生成了全基因组和转录组的数据集。转录组分析表明，分子亚型是由肿瘤内亚群混合驱动的基因表达连续体的产物，这已通过单细胞分析得到证实。综合全基因组分析发现，分子亚型与突变KRAS和GATA6等基因中的特定拷贝数畸变有关. 通过绘制肿瘤遗传史，四倍体化成为这些事件背后的关键突变过程。总之，这些数据支持这样一个前提，即肿瘤中的基因组畸变群导致了分子亚型，并且疾病异质性是由于进展过程中持续的基因组不稳定性造成的。