Highly complex genomic amplification arises from chromothripsis followed by circular recombination.

  • Major Finding: Highly complex genomic amplification arises from chromothripsis followed by circular recombination.

  • Concept: Repetitive recombination in circular extrachromosomal DNA creates complex amplification patterns.

  • Impact: This stepwise process underlies oncogene amplification and overexpression in many human tumor types.

Genomic amplification contributes to tumor progression by increasing gene copy number (CN) and elevating oncogene expression. Although genomic amplification is prevalent in many tumor types, the events that give rise to complex amplification patterns are not well understood. To investigate mechanisms of amplification, Rosswog, Bartenhagen, and colleagues analyzed whole-genome sequencing (WGS) data of tumor samples from patients with neuroblastoma and identified a type of complex amplification referred to as “seismic amplification,” characterized by a pattern of multiple rearrangements and numerous genomic segments with distinct CN states, interrupted by nonamplified or deleted regions. Analysis of cytogenetic state via fluorescence in situ hybridization revealed that seismic amplification could present as extrachromosomal double minutes (DM), intrachromosomal homogeneously staining regions (HSR), or neochromosomes (NC). Extending these observations beyond neuroblastoma, seismic amplification was detected in WGS data of almost 10% of patient tumors representing 38 cancer types and was distinguishable from other types of amplifications by increased maximum CN and RNA expression of affected oncogenes. Further analysis found that chromothripsis, a catastrophic mutational event that leads to chromosome rearrangement of a genomic region, was associated with seismic amplification in human tumors, suggesting that chromothripsis contributed in part to this process. Given that chromothripsis alone likely could not account for complex seismic amplicon structure, a progressive evolutionary model was proposed, in which seismic amplification is initiated by chromothripsis, producing DNA fragments which can undergo circularization, followed by cycles of circular recombination. After recombination, the amplicon can remain circular, integrate into a chromosome, or form an NC, stabilizing and presenting as DM, HSR, or NC, respectively. Read support of amplicon rearrangements supported this stepwise model, in addition to validation through computational simulations, as CN signatures observed in human tumors were similar to simulated amplifications in which chromothripsis was followed by circular recombination. In summary, this work describes a mechanism that gives rise to a highly complex type of genomic amplification that is pertinent to many tumor types.

Rosswog C, Bartenhagen C, Welte A, Kahlert Y, Hemstedt N, Lorenz W, et al. Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nat Genet 2021;53:1673–85.

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