Detecting and reconstructing breakage-fusion-bridge cycles from long-read sequencing using BFBArchitect
Chaohui Li1, Siavash Raeisi Dehkordi1, Daniel Muliaditan2
1Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, United States.
Bioinformatics (Oxford, England)
|July 7, 2026
Summary
BFBArchitect accurately distinguishes breakage-fusion-bridge (BFB) events from extrachromosomal DNA (ecDNA) using long-read sequencing. This computational tool reconstructs BFB sequences, offering insights into tumor progression and therapy resistance.
Area of Science:
- Genomics
- Computational Biology
- Cancer Research
Background:
- Focal oncogene amplification drives tumor progression, with extrachromosomal DNA (ecDNA) and intrachromosomal amplifications having distinct impacts.
- ecDNA amplifications are linked to tumor heterogeneity, therapy resistance, and poor prognosis.
- Intrachromosomal amplifications often result from breakage-fusion-bridge (BFB) cycles, leading to stable, rearranged chromosomes.
Purpose of the Study:
- To develop a computational method for distinguishing BFB from ecDNA using long-read sequencing data.
- To provide sequence-level reconstructions of BFB events for mechanistic insights.
Main Methods:
- Developed BFBArchitect, a computational tool leveraging long-read Oxford Nanopore data.
- Utilized a novel combinatorial characterization of BFB leading to integer linear programming (ILP) optimization.
- BFBArchitect analyzes copy number and structural variations to identify BFB sequences.
Main Results:
- BFBArchitect achieves near-perfect accuracy in distinguishing BFB from non-BFB structures in simulations and validated tumor samples.
- The tool generates sequence-level BFB reconstructions, revealing insights into repair mechanisms, template switching, and telomere recapture.
- Successfully applied to 18 validated tumor samples.
Conclusions:
- BFBArchitect is a robust computational tool for identifying and characterizing BFB events.
- The method aids in understanding the mechanisms of BFB formation and its role in cancer.
- Distinguishing BFB from ecDNA is crucial for understanding tumor progression and developing targeted therapies.
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