Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

具有复杂治疗史的晚期和转移性肿瘤会导致癌症死亡率。在这里，我们描述了 POG570 队列，这是一个全面的全基因组、转录组和临床数据集，可用于探索治疗对基因组景观的影响。先前暴露于破坏 DNA 的化学疗法和影响 DNA 修复基因的突变，包括POLQ和编码 Polζ 的基因，与全基因组、治疗诱导的诱变有关。暴露于铂疗法与签名 SBS31 和 DSB5 相吻合，当与 DNA 合成抑制剂结合时，签名 SBS17b。ESR1 、EGFR、CTNNB1、FGFR1、VEGFA和DPYD的变化与耐药性和敏感性一致。在TERT、PLEKHS1、AP2A1和ADGRG6等基因的调控区域热点中发现了反复发生的非编码事件。突变负荷和免疫特征与总生存期和对免疫治疗的反应相对应。我们的数据为研究晚期癌症以及在癌症诊所背景下解释全基因组和转录组测序提供了丰富的资源。