Aditi Gnanasekar

All Publications

• Breakage fusion bridge cycles drive high oncogene number with moderate intratumoural heterogeneity. Nature communications Raeisi Dehkordi, S., Wong, I. T., Ni, J., Luebeck, J., Zhu, K., Prasad, G., Krockenberger, L., Xu, G., Chowdhury, B., Rajkumar, U., Caplin, A., Muliaditan, D., Gnanasekar, A., Coruh, C., Jin, Q., Turner, K., Teo, S. X., Pang, A. W., Alexandrov, L. B., Chua, C. E., Furnari, F. B., Maciejowski, J., Paulson, T. G., Law, J. A., Chang, H. Y., Yue, F., DasGupta, R., Zhao, J., Mischel, P. S., Bafna, V. 2025; 16 (1): 1497

  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.

  View details for DOI 10.1038/s41467-025-56670-8

  View details for PubMedID 39929823

  View details for PubMedCentralID PMC11811125

• Coordinated inheritance of extrachromosomal DNAs in cancer cells. Nature Hung, K. L., Jones, M. G., Wong, I. T., Curtis, E. J., Lange, J. T., He, B. J., Luebeck, J., Schmargon, R., Scanu, E., Bruckner, L., Yan, X., Li, R., Gnanasekar, A., Chamorro Gonzalez, R., Belk, J. A., Liu, Z., Melillo, B., Bafna, V., Dorr, J. R., Werner, B., Huang, W., Cravatt, B. F., Henssen, A. G., Mischel, P. S., Chang, H. Y. 2024; 635 (8037): 201-209

  Abstract

  The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently1. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division2,3. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells4. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.

  View details for DOI 10.1038/s41586-024-07861-8

  View details for PubMedID 39506152