AmpliconReconstructor: Integrated analysis of NGS and optical mapping resolves the complex structures of focal amplifications in cancer

Luebeck, J.; Coruh, C.; Dehkordi, S. R.; Lange, J. T.; Turner, K. M.; Deshpande, V.; Pai, D. A.; Zhang, C.; Rajkumar, U.; Law, J. A.; Mischel, P. S.; Bafna, V.

doi:10.1101/2020.01.22.916031

bioRxiv · 10.1101/2020.01.22.916031

AmpliconReconstructor: Integrated analysis of NGS and optical mapping resolves the complex structures of focal amplifications in cancer

Luebeck, J.·Coruh, C.·Dehkordi, S. R.·Lange, J. T.·Turner, K. M.·Deshpande, V.·Pai, D. A.·Zhang, C.·Rajkumar, U.·Law, J. A.·Mischel, P. S.·Bafna, V.

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Abstract

Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary mechanism driving focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNAs structure is a first step in deciphering the mechanisms of its genesis and the subsequent biological consequences. Here, we introduce a powerful new computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating performance by extensive simulations, we used AR to reconstruct fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, breakage-fusion-bridge cycles, and other complex rearrangements. By distinguishing between chromosomal and extrachromosomal origins, and by reconstructing the rearrangement signatures associated with a given fCNAs generative mechanism, AR enables a more thorough understanding of the origins of fCNAs, and their functional consequences.

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Luebeck, J., Coruh, C., Dehkordi, S. R., Lange, J. T., Turner, K. M., Deshpande, V., Pai, D. A., Zhang, C., Rajkumar, U., Law, J. A., Mischel, P. S., Bafna, V.. 2020-01-23. AmpliconReconstructor: Integrated analysis of NGS and optical mapping resolves the complex structures of focal amplifications in cancer. https://doi.org/10.1101/2020.01.22.916031

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