Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity
Abstract Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remai...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56670-8 |
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| author | Siavash Raeisi Dehkordi Ivy Tsz-Lo Wong Jing Ni Jens Luebeck Kaiyuan Zhu Gino Prasad Lena Krockenberger Guanghui Xu Biswanath Chowdhury Utkrisht Rajkumar Ann Caplin Daniel Muliaditan Aditi Gnanasekar Ceyda Coruh Qiushi Jin Kristen Turner Shu Xian Teo Andy Wing Chun Pang Ludmil B. Alexandrov Christelle En Lin Chua Frank B. Furnari John Maciejowski Thomas G. Paulson Julie A. Law Howard Y. Chang Feng Yue Ramanuj DasGupta Jean Zhao Paul S. Mischel Vineet Bafna |
| author_facet | Siavash Raeisi Dehkordi Ivy Tsz-Lo Wong Jing Ni Jens Luebeck Kaiyuan Zhu Gino Prasad Lena Krockenberger Guanghui Xu Biswanath Chowdhury Utkrisht Rajkumar Ann Caplin Daniel Muliaditan Aditi Gnanasekar Ceyda Coruh Qiushi Jin Kristen Turner Shu Xian Teo Andy Wing Chun Pang Ludmil B. Alexandrov Christelle En Lin Chua Frank B. Furnari John Maciejowski Thomas G. Paulson Julie A. Law Howard Y. Chang Feng Yue Ramanuj DasGupta Jean Zhao Paul S. Mischel Vineet Bafna |
| author_sort | Siavash Raeisi Dehkordi |
| collection | DOAJ |
| description | Abstract Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remains poorly understood due to detection challenges with DNA sequencing. We introduce an algorithm, OM2BFB, designed to detect and reconstruct BFB amplifications using optical genome mapping (OGM). OM2BFB demonstrates high precision (>93%) and recall (92%) in identifying BFB amplifications across cancer cell lines, patient-derived xenograft models, and primary tumors. Comparisons using OGM reveal that BFB detection with our AmpliconSuite toolkit for short-read sequencing also achieves high precision, though with reduced sensitivity. We identify 371 BFB events through whole genome sequencing of 2557 primary tumors and cancer cell lines. BFB amplifications are prevalent in cervical, head and neck, lung, and esophageal cancers, but rare in brain cancers. Genes amplified through BFB exhibit lower expression variance, with limited potential for regulatory adaptation compared to ecDNA-amplified genes. Tumors with BFB amplifications (BFB(+)) show reduced structural heterogeneity in amplicons and delayed resistance onset relative to ecDNA(+) tumors. These findings highlight ecDNA and BFB amplifications as distinct oncogene amplification mechanisms with differing biological characteristics, suggesting distinct avenues for therapeutic intervention. |
| format | Article |
| id | doaj-art-28ab681fa4874eb3bce2a7057a8663c4 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-28ab681fa4874eb3bce2a7057a8663c42025-08-20T02:13:06ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56670-8Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneitySiavash Raeisi Dehkordi0Ivy Tsz-Lo Wong1Jing Ni2Jens Luebeck3Kaiyuan Zhu4Gino Prasad5Lena Krockenberger6Guanghui Xu7Biswanath Chowdhury8Utkrisht Rajkumar9Ann Caplin10Daniel Muliaditan11Aditi Gnanasekar12Ceyda Coruh13Qiushi Jin14Kristen Turner15Shu Xian Teo16Andy Wing Chun Pang17Ludmil B. Alexandrov18Christelle En Lin Chua19Frank B. Furnari20John Maciejowski21Thomas G. Paulson22Julie A. Law23Howard Y. Chang24Feng Yue25Ramanuj DasGupta26Jean Zhao27Paul S. Mischel28Vineet Bafna29Department of Computer Science and Engineering, University of California San DiegoDepartment of Pathology, Stanford University School of MedicineDepartment of Cancer Biology, Dana-Farber Cancer InstituteDepartment of Computer Science and Engineering, University of California San DiegoDepartment of Computer Science and Engineering, University of California San DiegoDepartment of Computer Science and Engineering, University of California San DiegoDepartment of Computer Science and Engineering, University of California San DiegoPlant Molecular and Cellular Biology Laboratory, Salk Institute for Biological StudiesDepartment of Computer Science and Engineering, University of California San DiegoDepartment of Computer Science and Engineering, University of California San DiegoDepartment of Computer Science and Engineering, University of California San DiegoGenome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)Department of Pathology, Stanford University School of MedicinePlant Molecular and Cellular Biology Laboratory, Salk Institute for Biological StudiesDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern UniversityBoundless BioSingapore Nuclear Research and Safety Initiative, National University of SingaporeBionano GenomicsMoores Cancer Center, UC San Diego HealthSingapore Nuclear Research and Safety Initiative, National University of SingaporeDepartment of Medicine, University of California at San DiegoMolecular Biology Program, Memorial Sloan Kettering Cancer CenterTranslational Science and Therapeutics Division, Fred Hutchinson Cancer CenterPlant Molecular and Cellular Biology Laboratory, Salk Institute for Biological StudiesCenter for Personal Dynamic Regulomes, Stanford UniversityDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern UniversityGenome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)Department of Cancer Biology, Dana-Farber Cancer InstituteDepartment of Pathology, Stanford University School of MedicineDepartment of Computer Science and Engineering, University of California San DiegoAbstract Oncogene amplification is a key driver of cancer pathogenesis. Both breakage fusion bridge (BFB) cycles and extrachromosomal DNA (ecDNA) can lead to high oncogene copy numbers, but the impact of BFB amplifications on intratumoral heterogeneity, treatment response, and patient survival remains poorly understood due to detection challenges with DNA sequencing. We introduce an algorithm, OM2BFB, designed to detect and reconstruct BFB amplifications using optical genome mapping (OGM). OM2BFB demonstrates high precision (>93%) and recall (92%) in identifying BFB amplifications across cancer cell lines, patient-derived xenograft models, and primary tumors. Comparisons using OGM reveal that BFB detection with our AmpliconSuite toolkit for short-read sequencing also achieves high precision, though with reduced sensitivity. We identify 371 BFB events through whole genome sequencing of 2557 primary tumors and cancer cell lines. BFB amplifications are prevalent in cervical, head and neck, lung, and esophageal cancers, but rare in brain cancers. Genes amplified through BFB exhibit lower expression variance, with limited potential for regulatory adaptation compared to ecDNA-amplified genes. Tumors with BFB amplifications (BFB(+)) show reduced structural heterogeneity in amplicons and delayed resistance onset relative to ecDNA(+) tumors. These findings highlight ecDNA and BFB amplifications as distinct oncogene amplification mechanisms with differing biological characteristics, suggesting distinct avenues for therapeutic intervention.https://doi.org/10.1038/s41467-025-56670-8 |
| spellingShingle | Siavash Raeisi Dehkordi Ivy Tsz-Lo Wong Jing Ni Jens Luebeck Kaiyuan Zhu Gino Prasad Lena Krockenberger Guanghui Xu Biswanath Chowdhury Utkrisht Rajkumar Ann Caplin Daniel Muliaditan Aditi Gnanasekar Ceyda Coruh Qiushi Jin Kristen Turner Shu Xian Teo Andy Wing Chun Pang Ludmil B. Alexandrov Christelle En Lin Chua Frank B. Furnari John Maciejowski Thomas G. Paulson Julie A. Law Howard Y. Chang Feng Yue Ramanuj DasGupta Jean Zhao Paul S. Mischel Vineet Bafna Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity Nature Communications |
| title | Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| title_full | Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| title_fullStr | Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| title_full_unstemmed | Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| title_short | Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| title_sort | breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity |
| url | https://doi.org/10.1038/s41467-025-56670-8 |
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