Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA.
Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS305, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep Med. 2023 Feb 21;4(2):100932. doi: 10.1016/j.xcrm.2023.100932. Epub 2023 Feb 1.
Molecular mechanisms underlying cancer metastasis span diverse tissues of origin. Here, we synthesize and collate the transcriptomes of patient-derived xenografts and patient tumor metastases, and these data collectively represent 38 studies and over 3,000 patients and 4,000 tumors. We identify four expression-based subtypes of metastasis transcending tumor lineage. The first subtype has extensive copy alterations, higher expression of MYC transcriptional targets and DNA repair genes, and bromodomain inhibitor response association. The second subtype has higher expression of genes involving metabolism and prostaglandin synthesis and regulation. The third subtype has evidence of neuronal differentiation, higher expression of DNA and histone methylation genes and EZH2 transcriptional targets, and BCL2 inhibitor response association. The fourth subtype has higher expression of immune checkpoint and Notch pathway genes. The metastasis subtypes reflect expression differences from paired primaries, with subtype switching being common. These subtypes facilitate understanding of the molecular underpinnings of metastases beyond tissue-oriented domains, with therapeutic implications.
癌症转移的分子机制跨越了不同的起源组织。在这里,我们综合整理了患者来源的异种移植物和患者肿瘤转移的转录组数据,这些数据共代表了 38 项研究,涉及超过 3000 名患者和 4000 个肿瘤。我们确定了四种基于表达的转移亚型,超越了肿瘤谱系。第一个亚型具有广泛的拷贝改变,更高的 MYC 转录靶基因和 DNA 修复基因表达,以及溴结构域抑制剂反应关联。第二个亚型具有更高的参与代谢和前列腺素合成和调节的基因表达。第三个亚型有神经元分化的证据,更高的 DNA 和组蛋白甲基化基因以及 EZH2 转录靶基因表达,以及 BCL2 抑制剂反应关联。第四个亚型有更高的免疫检查点和 Notch 通路基因表达。转移亚型反映了与配对原发性肿瘤的表达差异,亚型转换很常见。这些亚型有助于理解超越组织定向领域的转移的分子基础,具有治疗意义。