Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Cancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul 03080, Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea.
Cell Rep. 2023 Jul 25;42(7):112778. doi: 10.1016/j.celrep.2023.112778. Epub 2023 Jul 13.
The regulatory effect of non-coding large-scale structural variations (SVs) on proto-oncogene activation remains unclear. This study investigated SV-mediated gene dysregulation by profiling 3D cancer genome maps from 40 patients with colorectal cancer (CRC). We developed a machine learning-based method for spatial characterization of the altered 3D cancer genome. This revealed a frequent establishment of "de novo chromatin contacts" that can span multiple topologically associating domains (TADs) in addition to the canonical TAD fusion/shuffle model. Using this information, we precisely identified super-enhancer (SE)-hijacking and its clonal characteristics. Clonal SE-hijacking genes, such as TOP2B, are recurrently associated with cell-cycle/DNA-processing functions, which can potentially be used as CRC prognostic markers. Oncogene activation and increased drug resistance due to SE-hijacking were validated by reconstructing the patient's SV using CRISPR-Cas9. Collectively, the spatial and clonality-resolved analysis of the 3D cancer genome reveals regulatory principles of large-scale SVs in oncogene activation and their clinical implications.
非编码大规模结构变异 (SV) 对原癌基因激活的调控作用尚不清楚。本研究通过分析 40 例结直肠癌 (CRC) 患者的 3D 癌症基因组图谱，研究了 SV 介导的基因失调。我们开发了一种基于机器学习的方法来对改变的 3D 癌症基因组进行空间特征描述。这揭示了频繁建立“从头开始的染色质接触”，除了规范的 TAD 融合/重排模型外，还可以跨越多个拓扑关联域 (TAD)。利用这些信息，我们准确地识别了超级增强子 (SE) 劫持及其克隆特征。克隆 SE 劫持基因，如 TOP2B，与细胞周期/DNA 处理功能经常相关，这些基因可能可作为 CRC 预后标志物。通过使用 CRISPR-Cas9 重建患者的 SV，验证了 SE 劫持导致的致癌基因激活和药物耐药性增加。综上所述，对 3D 癌症基因组的空间和克隆分辨率分析揭示了大规模 SV 在致癌基因激活中的调控原则及其临床意义。
