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

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-10
DOI
https://doi.org/10.1038/s41467-025-56670-8
Citations
15
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
14.04

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article

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

Jing Ni, Andy Wing Chun Pang, Siavash R. Dehkordi, Qiushi Jin et al.
15 citations
Nature Communications
Cancer Genomics and Diagnostics
14.04
article

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

Jing Ni, Andy Wing Chun Pang, Siavash R. Dehkordi, Qiushi Jin, Ramanuj DasGupta, Lena Krockenberger, Biswanath Chowdhury, Ann H. Caplin, Gino Prasad, Vineet Bafna, Aditi Gnanasekar, Frank B. Furnari, Howard Y. Chang, Paul S. Mischel, Jean J. Zhao, Kristen M. Turner, Ivy Tsz-Lo Wong, Feng Yue, Guanghui Xu, Jens Luebeck, Thomas G. Paulson, Utkrisht Rajkumar, John Maciejowski, Ludmil B. Alexandrov, Daniel Muliaditan, Ceyda Çoruh, Julie A. Law, Shu Xian Teo, Kaiyuan Zhu, Christelle En Lin Chua
article en
15 citations

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.

Nature CommunicationsVol. 16(1)
Northwestern University (US), Agency for Science, Technology and Research (SG), Salk Institute for Biological Studies (US), Memorial Sloan Kettering Cancer Center (US), Howard Hughes Medical Institute (US), Harvard University (US), National University of Singapore (SG), UC San Diego Health System (US), Cancer Research UK (GB), University of California San Diego (US), Fred Hutch Cancer Center (US), Boundless Bio (United States) (US), BioNano Genomics (United States) (US), Dana-Farber Cancer Institute (US), Dana-Farber/Harvard Cancer Center (US), Stanford Medicine (US), Cancer Research UK Scotland Institute (GB), Genome Institute of Singapore (SG), University of Glasgow (GB), Stanford University (US)
Breast Cancer Research Foundation, Cancer Research UK, National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 1%
Cancer Genomics and Diagnostics
14.04
DOIOpen Access PDFOpenAlex
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