Chromosomal Rearrangements in Cancer Genomes

Chromosomal rearrangements constitute a major class of somatic alterations in cancer, encompassing deletions, duplications, inversions, translocations and complex phenomena such as chromothripsis and breakage–fusion–bridge cycles. These structural variants can delete tumour suppressors, amplify oncogenes or create fusion genes that drive malignant transformation. Mechanistically, DNA double-strand breaks arising from replication stress, mitotic errors or exogenous insults are processed by repair pathways such as non-homologous end joining, microhomology-mediated end joining and homologous recombination, generating diverse architectures. Complex events may occur in a single catastrophic episode or evolve stepwise, giving rise to circular extrachromosomal DNA elements and dicentric chromosomes that further fuel genomic instability. High-resolution whole-genome sequencing across multiple cancer types has revealed recurrent rearrangement signatures, tissue-specific biases and correlations with late-replicating regions. These insights have profound clinical implications: rearrangement profiles inform prognosis, reveal therapeutic vulnerabilities in DNA repair pathways and serve as biomarkers in liquid biopsies. Ongoing efforts aim to integrate structural variant landscapes with epigenetic and transcriptional data, yielding a more comprehensive view of tumour evolution and unveiling new strategies for targeted intervention.

Research from Nature Portfolio

Recent studies have elucidated mechanisms underlying focal oncogene amplification in breast cancer through a translocation–bridge amplification process. Inter-chromosomal translocations create dicentric chromosomes that undergo breakage–fusion cycles in mitosis, with resultant fragments often circularising as extrachromosomal DNA carrying amplified oncogenes such as ERBB2 and CCND1. Oestrogen-induced double-strand breaks at receptor binding sites initiate these translocations, demonstrating hormone-driven genome reshaping. Another investigation has defined the exclusive role of canonical non-homologous end joining in reassembling pulverised chromosomes following chromothripsis. By selectively disabling distinct repair pathways with CRISPR/Cas9, researchers showed that loss of key NHEJ components abolishes complex rearrangements and shifts outcomes towards simpler break re-ligation patterns. These findings highlight the centrality of NHEJ in generating the clustered structural variations characteristic of chromothripsis and underscore its potential as a therapeutic target in cancers harbouring catastrophic genome rearrangements.

Chromosomal Rearrangements in Cancer Genomes publication trend

The graph below shows the total number of articles in chromosomal rearrangements in cancer genomes across all publications each year (not limited to Nature Index journals).

Technical terms

Chromothripsis: Massive, clustered genomic rearrangements arising from a single catastrophic event.

Breakage–fusion–bridge (BFB) cycle: Iterative process of chromosome end fusion, bridge formation in mitosis and subsequent breakage.

Extrachromosomal DNA (ecDNA): Circular DNA fragments outside chromosomes that often carry amplified oncogenes.

Non-homologous end joining (NHEJ): DNA double-strand break repair pathway that ligates ends without extensive homology.

Dicentric chromosome: Chromosome containing two centromeres, prone to bridge formation and breakage.

Double-strand break (DSB): A lesion involving both strands of the DNA helix, initiating repair and potential rearrangement.

References

1. ERα-associated translocations underlie oncogene amplifications in breast cancer. Nature (2023).
2. Non-homologous end joining shapes the genomic rearrangement landscape of chromothripsis from mitotic errors. Nature Communications (2024).
3. Elucidation of the molecular mechanism of the breakage-fusion-bridge (BFB) cycle using a CRISPR-dCas9 cellular model. Nucleic Acids Research (2024).
4. Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. Cell (2011).
5. Patterns of somatic structural variation in human cancer genomes. Nature (2020).