Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cell Rep. 2019 Jan 8;26(2):496-506.e3. doi: 10.1016/j.celrep.2018.12.066.
We systematically investigated the landscape of tumor-suppressor gene (TSG) inactivation events in 33 cancer types by quantitatively measuring their global and local genomic features and their transcriptional and signaling footprints. Using The Cancer Genome Atlas data, we identified with high confidence 337 TSG × cancer events in 30 cancer types, of which 277 were unique events. The majority (91.0%) of these events had a significant downstream impact measured by reduced expression of the TSG itself (cis-effect), disturbance of the transcriptome (trans-effect), or combinatorial effects. Importantly, the transcriptomic changes associated with TSG inactivation events were stronger than the cancer lineage difference, and the same TSGs inactivated in different cancer types tended to cluster together. Several TSGs (e.g., RB1, TP53, and CDKN2A) involved in the regulation of the cell-cycle-formed clusters. Finally, we constructed subnetworks of the TSG × cancer inactivation events, including the local genes frequently disturbed upon the inactivation events.
我们通过定量测量 33 种癌症类型的全局和局部基因组特征及其转录和信号足迹，系统地研究了肿瘤抑制基因 (TSG) 失活事件的全景。使用癌症基因组图谱数据，我们在 30 种癌症类型中确定了 337 个 TSG×癌症事件，其中 277 个是独特事件。这些事件中的大多数（91.0%）通过 TSG 自身表达降低（顺式效应）、转录组紊乱（反式效应）或组合效应来衡量，都具有显著的下游影响。重要的是，与 TSG 失活事件相关的转录组变化强于癌症谱系差异，并且在不同癌症类型中失活的相同 TSG 往往聚集在一起。一些 TSG（如 RB1、TP53 和 CDKN2A）参与细胞周期的调节，形成了聚类。最后，我们构建了 TSG×癌症失活事件的子网，包括失活事件后经常受到干扰的局部基因。
