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Chromothripsis followed by circular recombination drives oncogene amplification in human cancer

Item Type:Article
Title:Chromothripsis followed by circular recombination drives oncogene amplification in human cancer
Creators Name:Rosswog, C. and Bartenhagen, C. and Welte, A. and Kahlert, Y. and Hemstedt, N. and Lorenz, W. and Cartolano, M. and Ackermann, S. and Perner, S. and Vogel, W. and Altmüller, J. and Nürnberg, P. and Hertwig, F. and Göhring, G. and Lilienweiss, E. and Stütz, A.M. and Korbel, J.O. and Thomas, R.K. and Peifer, M. and Fischer, M.
Abstract: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.
Keywords:Cancer, DNA Sequencing, Embryonal Neoplasms, Oncogenes
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:1673–1685
Date:December 2021
Official Publication:https://doi.org/10.1038/s41588-021-00951-7
PubMed:View item in PubMed

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