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

Kim, Kyukwang; Kim, Mooyoung; Lee, Andrew; Song, Sang‐Hyun; Kang, Jun-Kyu; Eom, Junghyun; Kang, Gyeong Hoon; Bae, Jeong Mo; Min, Sunwoo; Kim, Yeon Soo; Lim, Yoojoo; Kim, Han Sang; Kim, Young-Joon; Kim, Tae-You; Jung, Inkyung

doi:10.1016/j.celrep.2023.112778

Cited by 4 publications

(5 citation statements)

References 57 publications

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“…In addition, existing super-enhancers may become regulators of genes through copy number alterations (amplifications or deletions) that bring remote loci on the same chromosome in physical and functional proximity. For example, a long deletion produced a super-enhancer hijacking event in a colon cancer patient resulting in over-production of TOP2B [49]. After the patient's genomic lesion was introduced in HCT116 colorectal cancer cell line, the threedimensional genomic re-arrangement of the patient was reproduced and TOP2B was upregulated.…”

Section: Super-enhancer Hijacking In Cancermentioning

confidence: 99%

Targeting super-enhancer activity for colorectal cancer therapy

Voutsadakis

2024

Am J Transl Res

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In addition to genetic variants and copy number alterations, epigenetic deregulation of oncogenes and tumor suppressors is a major contributor in cancer development and propagation. Regulatory elements for gene transcription regulation can be found in promoters which are located in the vicinity of transcription start sites but also at a distance, in enhancer sites, brought to interact with proximal sites when occupied by enhancer protein complexes. These sites provide most of the specific regulatory sequences recognized by transcription factors. A subset of enhancers characterized by a longer structure and stronger activity, called super-enhancers, are critical for the expression of specific genes, usually associated with individual cell type identity and function. Super-enhancers show deregulation in cancer, which may have profound repercussions for cancer cell survival and response to therapy. Dysfunction of super-enhancers may result from multiple mechanisms that include changes in their sequence, alterations in the topological neighborhoods where they belong, and alterations in the proteins that mediate their function, such as transcription factors and epigenetic modifiers. These can become potential targets for therapeutic interventions. Genes that are targets of super-enhancers are cell and cancer type specific and could also be of interest for therapeutic targeting. In colorectal cancer, a super-enhancer regulated and over-expressed oncogene is MYC, under the influence of the WNT/β-catenin pathway. Identification and targeting of additional oncogenes regulated by super-enhancers in colorectal cancer may pave the way for combination therapies targeting the super-enhancer machinery and signal transduction pathways that regulate the specific transcription factors operative on them.

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Section: Super-enhancer Hijacking In Cancermentioning

confidence: 99%

Targeting super-enhancer activity for colorectal cancer therapy

Voutsadakis

2024

Am J Transl Res

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“… Year Studies 3D genome feature Type of cancer Refs. 2024 Ijaz, J. et al Chromothripsis Esophageal adenocarcinoma 113 2024 Achinger-Kawecka, J. et al Alteration of genome 3D structure associated with decitabine treatment Breast cancer 124 2023 Kim, K. et al Enhancer hijacking Colorectal cancer 110 2023 Erdmann-Pham, D. D. et al Somatic SVs Melanoma 17 2023 Song, T. et al Somatic SVs Adenocarcinoma 58 2023 Li, P. et al Alteration of genome 3D structure associated with oxaliplatin resistance Colorectal cancer 123 2022 Mallard et al Chromothripsis Leukemia 55 2022 Kim, T. et al CTCF Breast cancer 122 2022 Du, Y. et al Somatic SVs Pancreatic cancer 59 2021 Sunkel et al TF(ocoprotein)-driven chromatin loop Rhabdomyosarcoma 40 2021 Boone et al TF(ocoprotein)-driven chromatin loop Ewing sarcoma 41 2021 Iyyanki et al Altered chromatin loops associated with FOXA1 and GATA3 Bladder cancer 49 2021 Montefiori et al Enhancer hijacking Leukemia 54 ...…”

Section: Recent Cancer Studies From the Perspective Of Chromatin Stru...mentioning

confidence: 99%

“…Kim et al 110 revealed a pivotal insight: recurrent enhancer hijacking, orchestrated by SVs, can instigate a surge in oncogenic expression, all without a pronounced surge in CNVs. This discovery further underscores the indispensable role of Hi-C data in revealing the intricate web of oncogenic regulation in cancer, thereby shedding light on the multifaceted mechanisms driving cancer development and progression.…”

Section: Detection Of Structural Variants That Drive Oncogene Activationmentioning

confidence: 99%

“…Haplotype phasing can be performed either statistically or experimentally. The statistical method relies on population genetic data and linkage disequilibrium but may introduce errors at recombination hotspots 110 . In contrast, experimental phasing uses multiple variants within sequencing reads but faces challenges owing to the limited prevalence of heterozygous polymorphisms 111 .…”

Section: Reconstruction Of Complex Genomic Rearrangements At the Hapl...mentioning

confidence: 99%

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3C methods in cancer research: recent advances and future prospects

Yoon,

Kim,

Song

et al. 2024

Exp Mol Med

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In recent years, Hi-C technology has revolutionized cancer research by elucidating the mystery of three-dimensional chromatin organization and its role in gene regulation. This paper explored the impact of Hi-C advancements on cancer research by delving into high-resolution techniques, such as chromatin loops, structural variants, haplotype phasing, and extrachromosomal DNA (ecDNA). Distant regulatory elements interact with their target genes through chromatin loops. Structural variants contribute to the development and progression of cancer. Haplotype phasing is crucial for understanding allele-specific genomic rearrangements and somatic clonal evolution in cancer. The role of ecDNA in driving oncogene amplification and drug resistance in cancer cells has also been revealed. These innovations offer a deeper understanding of cancer biology and the potential for personalized therapies. Despite these advancements, challenges, such as the accurate mapping of repetitive sequences and precise identification of structural variants, persist. Integrating Hi-C with multiomics data is key to overcoming these challenges and comprehensively understanding complex cancer genomes. Thus, Hi-C is a powerful tool for guiding precision medicine in cancer research and treatment.

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“…Recently, also in colorectal cancer (CRC) patients, SVs-mediated 3D genome dysregulation was found to cause super enhancers (SE) elements hijacking, leading to the hyper-activation of TOP2B and CHEK1 genes. These genes are linked to genome instability and DNA repair mechanisms and their high expression is thought to sustain tumor cells survival and proliferation, making these SE-hijacking events tumor promoting, representing new potential therapeutic targets (Kim et al, 2023). Also in gastric cancers, an integrated paired-end NanoChIP-seq (PeNChIP-seq) combined with whole genome sequencing (WGS) approach revealed new tumor-associated regulatory SVs-mediated enhancers hijacking, in regions associated with both simple and complex genomic rearrangements.…”

Section: Dna Regulatory Elements Dysfunction In Cancer: Enhancer Hija...mentioning

confidence: 99%

Enhancers dysfunction in the 3D genome of cancer cells

Della Chiara,

Jiménez,

Virdi

et al. 2023

Front. Cell Dev. Biol.

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Eukaryotic genomes are spatially organized inside the cell nucleus, forming a threedimensional (3D) architecture that allows for spatial separation of nuclear processes and for controlled expression of genes required for cell identity specification and tissue homeostasis. Hence, it is of no surprise that mis-regulation of genome architecture through rearrangements of the linear genome sequence or epigenetic perturbations are often linked to aberrant gene expression programs in tumor cells. Increasing research efforts have shed light into the causes and consequences of alterations of 3D genome organization. In this review, we summarize the current knowledge on how 3D genome architecture is dysregulated in cancer, with a focus on enhancer highjacking events and their contribution to tumorigenesis. Studying the functional effects of genome architecture perturbations on gene expression in cancer offers a unique opportunity for a deeper understanding of tumor biology and sets the basis for the discovery of novel therapeutic targets.

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

Cited by 4 publications

References 57 publications

Targeting super-enhancer activity for colorectal cancer therapy

Targeting super-enhancer activity for colorectal cancer therapy

3C methods in cancer research: recent advances and future prospects

Enhancers dysfunction in the 3D genome of cancer cells

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