Mapping extrachromosomal DNA amplifications during cancer progression
To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis.
Authors
- Anuja Lipsa (ORCID: https://orcid.org/0000-0002-9668-6048)
- Taylor E. Wade (ORCID: https://orcid.org/0000-0003-3975-4769)
- Vineet Bafna (ORCID: https://orcid.org/0000-0002-5810-6241)
- Hyo-Eun Moon
- Anna Golebiewska (ORCID: https://orcid.org/0000-0002-4160-2521)
- Roel G.W. Verhaak (ORCID: https://orcid.org/0000-0003-2773-0436)
- Simone P. Niclou (ORCID: https://orcid.org/0000-0002-3417-9534)
- JJ Ko
- Sun Ha Paek (ORCID: https://orcid.org/0000-0003-3007-8653)
- Eunchae Yeo
- Jens Luebeck (ORCID: https://orcid.org/0000-0003-4391-979X)
- Kevin C. Johnson (ORCID: https://orcid.org/0000-0003-0016-5158)
- Hoon Kim (ORCID: https://orcid.org/0000-0003-4244-6126)
- H. Lee (ORCID: https://orcid.org/0000-0001-7419-8994)
- Hesson Chung
- Sun-Young An
- Soyeon Kim (ORCID: https://orcid.org/0009-0004-6509-5490)
- Y.H. Nam
- So-Young Kang (ORCID: https://orcid.org/0009-0002-6481-310X)
Institutions
- University of Luxembourg (LU)
- Seoul National University Hospital (KR)
- Yale University (US)
- University of California San Diego (US)
- Luxembourg Institute of Health (LU)
- Luxembourg Institute of Science and Technology (LU)
- Jackson Laboratory (US)
- Advanced Institute of Convergence Technology (KR)
- Amsterdam University Medical Centers (NL)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1038/s41588-024-01949-7
- Citations
- 43
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 12.26