Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change.

Autor: Dehkordi SR; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Wong IT; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Ni J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA., Luebeck J; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA.; Bioinformatics and Systems Biology Graduate Program, University of California San Diego, San Diego, CA, USA., Zhu K; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Prasad G; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Krockenberger L; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Xu G; Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Chowdhury B; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Rajkumar U; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Caplin A; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA., Muliaditan D; Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Coruh C; Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.; ClearNote Health, San Diego, CA 92121 USA., Jin Q; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA., Turner K; Boundless Bio, San Diego, CA, USA., Teo SX; Singapore Nuclear Research and Safety Initiative, National University of Singapore., Pang AWC; Bionano Genomics, San Diego, CA92121, USA., Alexandrov LB; Moores Cancer Center, UC San Diego Health, La Jolla, CA, USA.; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.; Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA., Chua CEL; Singapore Nuclear Research and Safety Initiative, National University of Singapore., Furnari FB; Department of Medicine, University of California at San Diego, La Jolla, CA, USA., Paulson TG; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Law JA; Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.; Division of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA., Yue F; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA., DasGupta R; Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Zhao J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA., Mischel PS; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Bafna V; Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA.; Halıcıoğlu Data Science Institute, University of California at San Diego, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 13. Date of Electronic Publication: 2023 Dec 13.
DOI: 10.1101/2023.12.12.571349
Abstrakt: Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.
Databáze: MEDLINE