Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
Cell Rep. 2021 Nov 16;37(7):110023. doi: 10.1016/j.celrep.2021.110023.
The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.
体细胞结构变异 (SVs) 对具有复杂治疗史的晚期肿瘤中基因调控的全球影响在很大程度上尚未可知。在这里，我们使用来自 570 个复发性或转移性肿瘤的全基因组和 RNA 测序，报告了数百个与附近 SV 断点相关的基因表达改变，包括癌基因和 G 蛋白偶联受体相关基因，如 PLEKHG2。与 SV 表达关联的基因中有相当一部分与原发性和晚期癌症患者的生存预后较差相关，包括 SRD5A1。在许多情况下，SV 表达关联涉及逆转座子在基因附近易位。高总 SV 负担与 DNA 烷化剂或紫杉烷类药物治疗以及与代谢相关基因的表达改变有关。拓扑异构酶 I 抑制剂治疗患者肿瘤内的 SV 表达关联包括染色质相关基因。在蒽环类药物治疗的肿瘤中，染色体 1p 基因附近的 SV 断点包括 PDE4B。患者治疗和病史有助于了解在癌症中发现的广泛的 SV 介导的顺式调控改变。
