Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity

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 () and Vineet Bafna ()
Additional contact information
Siavash Raeisi Dehkordi: University of California San Diego
Ivy Tsz-Lo Wong: Stanford University School of Medicine
Jing Ni: Dana-Farber Cancer Institute
Jens Luebeck: University of California San Diego
Kaiyuan Zhu: University of California San Diego
Gino Prasad: University of California San Diego
Lena Krockenberger: University of California San Diego
Guanghui Xu: Salk Institute for Biological Studies
Biswanath Chowdhury: University of California San Diego
Utkrisht Rajkumar: University of California San Diego
Ann Caplin: University of California San Diego
Daniel Muliaditan: Technology and Research (A*STAR)
Aditi Gnanasekar: Stanford University School of Medicine
Ceyda Coruh: Salk Institute for Biological Studies
Qiushi Jin: Feinberg School of Medicine Northwestern University
Kristen Turner: Boundless Bio
Shu Xian Teo: National University of Singapore
Andy Wing Chun Pang: Bionano Genomics
Ludmil B. Alexandrov: UC San Diego Health
Christelle En Lin Chua: National University of Singapore
Frank B. Furnari: University of California at San Diego
John Maciejowski: Memorial Sloan Kettering Cancer Center
Thomas G. Paulson: Fred Hutchinson Cancer Center
Julie A. Law: Salk Institute for Biological Studies
Howard Y. Chang: Stanford University
Feng Yue: Feinberg School of Medicine Northwestern University
Ramanuj DasGupta: Technology and Research (A*STAR)
Jean Zhao: Dana-Farber Cancer Institute
Paul S. Mischel: Stanford University School of Medicine
Vineet Bafna: University of California San Diego

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56670-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56670-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56670-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().