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The breakage–fusion–bridge (BFB) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma

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Abstract

Osteosarcoma (OS) is characterized by chromosomal instability and high copy number gene amplification. The breakage–fusion–bridge (BFB) cycle is a well-established mechanism of genome instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. To determine whether the BFB cycle could be increasing the de novo rate of formation of cytogenetic aberrations in OS, the frequency of anaphase bridge configurations and dicentric chromosomes in four OS cell lines was quantified. An increased level of anaphase bridges and dicentrics was observed in all the OS cell lines. There was also a strong association between the frequencies of anaphase bridges, dicentrics, centrosomal anomalies, and multipolar mitotic figures in all the OS cell lines, indicating a possible link in the mechanisms that led to the structural and numerical instabilities observed in OS. In summary, this study has provided strong support for the role of the BFB cycle in generating the extensive structural chromosome aberrations, as well as cell-to-cell cytogenetic variation observed in OS, thus conferring the genetic diversity for OS tumor progression.

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Acknowledgement

This work was supported by funding from the National Cancer Institute of Canada and Canadian Institute of Health Research (Ph.D. fellowship to S.S.).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Shamini Selvarajah, Gloria Lim & Maria Zielenska

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5G 1L5, Canada

    Shamini Selvarajah, Khaldoun Al-Romaih, Jeremy A. Squire & Maria Zielenska

  3. Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Room 9-721, Toronto, ON, M5G 2M9, Canada

    Maisa Yoshimoto, Georges Maire, Jana Paderova, Jane Bayani, Khaldoun Al-Romaih & Jeremy A. Squire

  4. Department of Pathology and Laboratory Medicine and Pathobiology, Ottawa General Hospital, Ottawa, ON, K1H 8L6, Canada

    Paul C. Park

  5. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, M5G 2M9, Canada

    Jeremy A. Squire

Authors
  1. Shamini Selvarajah
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  2. Maisa Yoshimoto
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  3. Paul C. Park
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  4. Georges Maire
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  6. Jane Bayani
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  7. Gloria Lim
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  8. Khaldoun Al-Romaih
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  9. Jeremy A. Squire
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  10. Maria Zielenska
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Corresponding author

Correspondence to Jeremy A. Squire.

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Communicated by E.A. Nigg

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Selvarajah, S., Yoshimoto, M., Park, P.C. et al. The breakage–fusion–bridge (BFB) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma. Chromosoma 115, 459–467 (2006). https://doi.org/10.1007/s00412-006-0074-4

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  • DOI: https://doi.org/10.1007/s00412-006-0074-4

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