Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity
Siavash R. Dehkordi, Ivy Tsz-Lo Wong, Jing Ni, Jens Luebeck, Kaiyuan Zhu, Gino Prasad, Lena Krockenberger, Guanghui Xu, Biswanath Chowdhury, Utkrisht Rajkumar, Ann H. Caplin, Daniel Muliaditan, Aditi Gnanasekar, Ceyda Çoruh, Qiushi Jin, Kristen M. 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 J. Zhao, Paul S. Mischel, Vineet Bafna
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.