The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. Using whole-genome sequencing data of the pediatric tumor neuroblastoma, we here identified a type of amplification, termed ‘seismic amplification’, that is characterized by multiple rearrangements and discontinuous copy number levels. Overall, seismic amplifications occurred in 9.9% (274 of 2,756) of cases across 38 cancer types, and were associated with massively increased copy numbers and elevated oncogene expression. Reconstruction of the development of seismic amplification showed a stepwise evolution, starting with a chromothripsis event, followed by formation of circular extrachromosomal DNA that subsequently underwent repetitive rounds of circular recombination. The resulting amplicons persisted as extrachromosomal DNA circles or had reintegrated into the genome in overt tumors. Together, our data indicate that the sequential occurrence of chromothripsis and circular recombination drives oncogene amplification and overexpression in a substantial fraction of human malignancies.

癌症中复杂基因组扩增进化背后的机制在很大程度上仍不清楚。使用儿科肿瘤神经母细胞瘤的全基因组测序数据，我们在这里确定了一种扩增类型，称为“地震扩增”，其特征是多重重排和不连续的拷贝数水平。总体而言，地震放大发生在 38 种癌症类型的 9.9%（2,756 例中的 274 例）病例中，并且与大量增加的拷贝数和升高的癌基因表达有关。地震放大发展的重建显示出逐步演变，从染色体碎裂事件开始，随后形成环状染色体外 DNA，随后经历重复的循环重组。由此产生的扩增子作为染色体外 DNA 环持续存在，或者在明显的肿瘤中重新整合到基因组中。总之，我们的数据表明，在相当一部分人类恶性肿瘤中，染色体碎裂和循环重组的连续发生驱动致癌基因扩增和过度表达。