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Structural variations in cancer and the 3D genome

Abstract

Structural variations (SVs) affect more of the cancer genome than any other type of somatic genetic alteration but difficulties in detecting and interpreting them have limited our understanding. Clinical cancer sequencing also increasingly aims to detect SVs, leading to a widespread necessity to interpret their biological and clinical relevance. Recently, analyses of large whole-genome sequencing data sets revealed features that impact rates of SVs across the genome in different cancers. A striking feature has been the extent to which, in both their generation and their influence on the selective fitness of cancer cells, SVs are more specific to individual cancer types than other genetic alterations such as single-nucleotide variants. This Perspective discusses how the folding of the 3D genome, and differences in its folding across cell types, affect observed SV rates in different cancer types as well as how SVs can impact cancer cell fitness.

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Fig. 1: Types of genomic rearrangements.
Fig. 2: Chromatin organization and its disruption by rearrangements in cancer.
Fig. 3: Mechanistic biases of structural variation formation.
Fig. 4: Structural variation effects on cellular fitness in cancer.

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Acknowledgements

This work was supported by the Independent Research Fund Denmark (0134-00265B; J.W. and N.S.), the German Research Foundation (DFG) (F.D.) and the National Institutes of Health (NIH), the Paediatric Brain Tumour Foundation, the Fund for Innovative Cancer Informatics and the Gray Matters Brain Cancer Foundation (R.B.).

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Correspondence to Joachim Weischenfeldt or Rameen Beroukhim.

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Related links

SVscape: http://svscape.com/

Glossary

‘A’ compartments

Cell type-specific megabase-scale organizations of the 3D genome associated with open chromatin and active transcript DNA.

Breakage–fusion–bridge cycles

A mechanism of amplification in cancer genomes whereby chromosomes fuse due to telomere shortening and get broken apart during mitosis, leaving one daughter cell with extra copies of genes.

Chromatin compartments

Subdivisions of chromosome territories divided into compartments with open and closed chromatin.

Chromatin loop anchors

Protein complexes including CCCTC binding factor (CTCF) and cohesin that contribute to organizing the 3D structure of the genome.

Chromoanasynthesis

A mechanism of complex structural variation (SV) generation due to template switching during replication.

Chromoplexy

Chains of structural variations (SVs) involving multiple chromosomes.

Chromosome territories

Discrete regions within the nucleus containing a specific chromosome.

Chromothripsis

A mechanism of structural variation (SV) generation involving the shattering of a chromosome and random reassembly of DNA fragments, leading to a complex pattern of step-like copy number changes alternating between two, and sometimes three, states.

Discordant reads

Paired-end sequencing reads where the distance separating the pair or their orientation differs from that expected.

Driver events

Genetic variants resulting in increased evolutionary fitness of the affected cell.

Evolutionary selection

In cancer, the process of enrichment of subclones with increased fitness within a clonal cell population.

Extrachromosomal amplification

A small circular fragment of DNA that is randomly distributed during mitosis. Extrachromosomal amplifications can reach very high copy numbers, usually because they encode an oncogene and undergo positive selection.

Hi-C

A proximity ligation-based sequencing technology that, in principle, allows the detection of all 3D interactions between DNA segments in the nucleus.

Homologous recombination

A relatively error-free DNA double-strand break (DSB) repair pathway involving a repair template (typically the homologous chromosome).

Mechanistic biases

Differences in the background probability with which structural variations (SVs) will form at different loci in a particular cell type. This refers to the rate at which SVs form rather than the rate at which they are observed after undergoing evolutionary selection.

Microhomology-mediated break-induced replication

A form of microhomology-mediated template switching during replication, which can lead to a complex structural variation (SV) pattern.

Microhomology-mediated end-joining

A pathway for the repair of DNA double-strand breaks (DSBs) using microhomologous sequences at the break end to facilitate rejoining. Microhomology-mediated end-joining errors typically result in deletions.

Non-homologous end-joining

A repair pathway for DNA double-strand breaks (DSBs) that does not involve a repair template. This can be more error-prone than homology-based repair mechanisms.

Passenger events

Genetic variants with no positive effect on the evolutionary fitness of the affected cell that are nevertheless clonal in individual cancers, often due to positive selection resulting from driver events in the same cell.

Phase separation

A phenomenon of decreased mixing between molecules because of differences in the intermolecular interactions. Most familiar from separation of mixed oil and water, phase separation is now understood to be a mechanism by which transcriptional complexes form.

Punctuated evolution

Bursts of changes to the genome, with many variants acquired in one event, that can result in dramatical changes in evolutionary fitness. Punctuated evolution is often contrasted with the sequential acquisition and selection of individual variants in classic evolutionary theory.

Split reads

A sequencing read that comprises different sequences that align to different loci in the reference genome.

Templated insertions

Structural variations (SVs) in which a sequence from a distant genomic locus is inserted between two break points.

Topologically associated domains

(TADs). Regions in the genome in the range of hundreds to thousands of kilobases that are separated by boundary elements and show higher 3D interaction frequencies within the TAD than between TADs.

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Dubois, F., Sidiropoulos, N., Weischenfeldt, J. et al. Structural variations in cancer and the 3D genome. Nat Rev Cancer (2022). https://doi.org/10.1038/s41568-022-00488-9

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