Rosswog, Carolina, Bartenhagen, Christoph, Welte, Anne, Kahlert, Yvonne, Hemstedt, Nadine, Lorenz, Witali, Cartolano, Maria, Ackermann, Sandra ORCID: 0000-0002-5869-7344, Perner, Sven, Vogel, Wenzel, Altmueller, Janine, Nuernberg, Peter, Hertwig, Falk, Goehring, Gudrun, Lilienweiss, Esther, Stuetz, Adrian M., Korbel, Jan O., Thomas, Roman K., Peifer, Martin and Fischer, Matthias (2021). Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nature Genet., 53 (12). S. 1673 - 1706. BERLIN: NATURE PORTFOLIO. ISSN 1546-1718

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Abstract

Seismic amplifications arise from several cycles of circular recombination of circular extrachromosomal DNA formed as a result of chromothripsis. The process provides a mechanism for oncogene amplification in a number of different human tumor types. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rosswog, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welte, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kahlert, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemstedt, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, WitaliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cartolano, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ackermann, SandraUNSPECIFIEDorcid.org/0000-0002-5869-7344UNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, WenzelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertwig, FalkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goehring, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lilienweiss, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stuetz, Adrian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korbel, Jan O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-601147
DOI: 10.1038/s41588-021-00951-7
Journal or Publication Title: Nature Genet.
Volume: 53
Number: 12
Page Range: S. 1673 - 1706
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOGENEOUSLY STAINING REGIONS; GENE AMPLIFICATION; GENOMIC REARRANGEMENT; SOMATIC REARRANGEMENT; MUTATIONAL PROCESSES; TUMOR; EVOLUTION; NEUROBLASTOMA; HETEROGENEITY; CHROMOSOMESMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60114

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