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

doi:10.1016/j.celrep.2023.112778

Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer

Cell Rep. 2023 Jul 25;42(7):112778. doi: 10.1016/j.celrep.2023.112778. Epub 2023 Jul 13.

Authors

Affiliations

¹ Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
² 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.
³ Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea.
⁴ Cancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul 03080, Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
⁵ 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.
⁶ Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
⁷ 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. Electronic address: kimty@snu.ac.kr.
⁸ Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. Electronic address: ijung@kaist.ac.kr.

PMID: 37453058
DOI: 10.1016/j.celrep.2023.112778

Abstract

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.

Keywords: 3D cancer genome; CP: Cancer; CP: Genomics; clonality; colorectal cancer; enhancer-hijacking; in situ Hi-C; prognostic marker; structural variations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatin
Colorectal Neoplasms* / genetics
DNA
Genome*
Humans
Prognosis

Substances

Chromatin
DNA