The three-dimensional (3D) spatial organization of the human genome plays a crucial role in maintaining normal cellular function and proper gene regulation. Studies on chromatin conformation in the past decade have revealed different scales of genomic organization, with unique transcriptional consequences that range from individual genes to large clusters of co-ordinated expression 1, 2, 3, 4, 5. Briefly, chromatin loops occur when distant loci on the linear genome frequently contact each other in 3D nuclear space. The sizes of chromatin loops range from several kilobases to megabases, and they can be broadly categorized into two types 6, 7•: structural loops, which connect the CCCTC-binding factor (CTCF)-bound insulators, and regulatory loops, which link gene promoters to distal cis-regulatory elements such as enhancers or silencers and are commonly associated with gene regulation. At the hundreds of kilobases scale, chromatin is organized into topologically associating domains (TADs) 8, 9, where chromatin contacts are more enriched within a TAD than across TAD boundaries. Similar to loops, there are at least two types of TAD boundaries 7•, 10: one enriched with CTCF and Cohesin-binding sites and the other enriched with transcribed genes. Finally, the genome can be broadly divided into two compartments [11], an open and relatively active ‘A’ compartment and a closed and relatively inactive ‘B’ compartment. More recent work has shown the existence of subcompartments [12], and algorithms such as SNIPER [13] have been proposed to catch such multilayered structure. As there have been many excellent reviews of 3D genome in normal tissues and developmental stages 1, 2, 3, 4, 5, 14, 15, 16, this review is more focused on recent findings specifically in cancer.

In recent years, there has been a growth spurt in the availability of Hi-C (a high-throughput chromatin conformation capture technology) data in cancer. It has been shown that cancer genomes undergo substantial changes in 3D genome organization, and these changes can be associated with malignant progression across the spectrum 17, 18, 19, 20, 21•, 22•, 23, 24, 25. TADs and chromatin compartments might undergo significant alterations due to genetic or epigenetic changes in cancer, leading to profound changes in the cancer gene regulatory landscape. In addition, there has been a flourish of works describing the alterations of 3D genome organization induced by genomic rearrangements or structural variations (SVs) in cancer genomes. Apart from more established mechanisms such as the deletion of tumor suppressor genes, the amplification of proto-oncogenes, and the formation of oncogenic fusion genes, emerging evidence underscores that SVs can directly contribute to tumorigenesis by disrupting 3D genome architecture. In particular, SVs have been shown to bring distal enhancers or silencers into close proximity with cancer-related genes, sometimes from another chromosome, resulting in the dysregulation of gene expressions through processes termed as ‘enhancer hijacking’ 26, 27, 28 or ‘silencer hijacking’ [22].

Here, we provide an overview of recent insights into the alterations of 3D genome organization and gene regulation in cancer, particularly those induced by SVs. We also discuss the clinical implications of these findings and some of the challenges ahead in this field.