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.
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Volume | 53 |
| Issue number | 12 |
| Pages (from-to) | 1673-1685 |
| Number of pages | 13 |
| ISSN | 1061-4036 |
| DOIs | |
| Publication status | Published - 12.2021 |
Funding
Hagedorn, D. Schmitz and S. Hippler for their technical assistance with FISH, G-banding and m-FISH, D. Nöhrling for her contribution to rearrangement validation and H. C. Reinhardt for critical reading of the manuscript. We further thank C. Becker and M. Franitza for their support with linked-read sequencing and Bionano optical mapping. We thank the CECAD Imaging Facility for their support with microscopy. This work was funded through the Else Kröner-Fresenius Stiftung (2016-Kolleg-19 to C.R.), the Deutsche Forschungsgemeinschaft (DFG; grant no. BA 6984/1-1 to C.B., and FI 1926/2-1 to M.F.), the Förderverein für Krebskranke Kinder e.V. Köln (endowed chair to M.F.), the Fördergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V. (to M.F.), the German Cancer Aid (Mildred-Scheel professorship to M.P.), the German Ministry of Science and Education (BMBF) as part of the e:Med initiative (grant no. 01ZX1303 and 01ZX1603 to R.K.T., M.P, and M.F.; grant no. 01ZX1901 to R.K.T. and M.P; grant no. 01ZX1307 and 01ZX1607 to M.F.), the DFG as part of the KFO286 to M.P. and the SFB1399 (to R.K.T., M.P., and M.F.). Additional support was received by the DFG Research Infrastructure as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the production site WGGC Cologne.
