Publication in Nature Genetics


Study on the evolution of complex genomic amplifications in cancer

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The mechanisms behind the evolution of complex genomic amplifications in cancer have been poorly understood to date. Members of the CRC 1399 identified a type of amplification that they term “seismic amplification”, which is characterized by multiple rearrangements and numerous genomic segments amplified at distinct levels. “We found that seismic amplifications occurred frequently in human cancer, affecting roughly 10% of the cases in a cohort of more than 2,700 tumors across 38 cancer types”, explains Dr. Carolina Rosswog, first-author of the study and clinician scientist in the department of Experimental Pediatric Oncology and Pediatric Oncology and Hematology. Detailed reconstruction of the development of seismic amplification revealed a stepwise evolution behind these alterations, starting with a singular event of chromothripsis, followed by formation of extrachromosomal circular DNAs that subsequently underwent repetitive rounds of circular recombination. In overt tumors, the resulting amplified regions persisted as extrachromosomal DNA circles or had reintegrated into the genome, and did not substantially change at relapse, suggesting that seismic amplifications are stable events. “We found that seismic amplifications were associated with the occurrence of chromothripsis across cancer types and chromosomes, thus supporting our hypothesis of chromothripsis as the initiating event in the evolution of these alterations”, says Dr. Christoph Bartenhagen, computer scientist and co-first-author of the study. They also observed that genomic loci affected by seismic amplification frequently covered proto-oncogenes, such as CCND1 (chromosome 11q), CDK4, MDM2 (both chromosome 12q), and ERBB2 (chromosome 17q). Importantly, seismic amplification led to excess copy numbers and massive over-expression of these genes in comparison to other amplification types or non-amplified states.

Together, the data provide strong evidence that seismic amplification is a frequent event in cancer and follows a common evolutionary path, which is based on a stepwise evolution involving an initial chromothripsis event and subsequent recombination of extrachromosomal circular DNAs. “Importantly, our data corroborate that seismic amplification defines a subgroup of highly complex genomic alterations that is not covered by current categories of structural variations in cancer”, explains Prof. Matthias Fischer, head of the Department of Experimental Pediatric Oncology and last-author of the study. The study therefore provides novel insights into the mechanisms of how human tumors acquire genomic amplifications as major drivers of oncogenic transformation.

DOI: 10.1038/s41588-021-00951-7