Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer
Kyukwang Kim,
Mooyoung Kim,
Andrew J. Lee,
Sang-Hyun Song,
Jun-Kyu Kang,
Junghyun Eom,
Gyeong Hoon Kang,
Jeong Mo Bae,
Sunwoo Min,
Yeonsoo Kim,
Yoojoo Lim,
Han Sang Kim,
Young-Joon Kim,
Tae-You Kim,
Inkyung Jung
Affiliations
Kyukwang Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Mooyoung Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Andrew J. Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Sang-Hyun Song
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
Jun-Kyu Kang
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
Junghyun Eom
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Gyeong Hoon Kang
Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea
Jeong Mo Bae
Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea
Sunwoo Min
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Yeonsoo Kim
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
Yoojoo Lim
Cancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul 03080, Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea
Han Sang Kim
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea
Young-Joon Kim
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
Tae-You Kim
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; Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea; IMBdx, Inc., Seoul 08506, Korea; Corresponding author
Inkyung Jung
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea; Corresponding author
Summary: 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.
