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Profiling genomic copy number changes in retinoblastoma beyond loss of RB1

Authors

  • Ella Bowles,

    1. Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
    2. Department of Zoology, University of British Columbia, Vancouver, BC, Canada
    3. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
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    • These authors contributed equally to this work.

  • Timothy W. Corson,

    1. Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
    2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON, Canada
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    • These authors contributed equally to this work.

  • Jane Bayani,

    1. Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
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  • Jeremy A. Squire,

    1. Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
    2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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  • Nathalie Wong,

    1. Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, N. T., SAR Hong Kong, China
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  • Paul B.-S. Lai,

    1. Department of Surgery, Chinese University of Hong Kong, Shatin, N. T., SAR Hong Kong, China
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  • Brenda L. Gallie

    Corresponding author
    1. Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
    2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    3. Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON, Canada
    4. Department of Ophthalmology, University of Toronto, Toronto, ON, Canada
    • Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Room 8-415, 610 University Avenue, Toronto, ON M5G 2M9, Canada
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Abstract

Loss of both RB1 alleles is rate limiting for development of retinoblastoma (RB), but genomic copy number gain or loss may impact oncogene(s) and tumor suppressor genes, facilitating tumor progression. We used quantitative multiplex polymerase chain reaction to profile “hot spot” genomic copy number changes for gain at 1q32.1, 6p22, and MYCN, and loss at 16q22 in 87 primary RB and 7 cell lines. Loss at 16q22 (48%) negatively associated with MYCN gain (18%) (Fisher's exact P = 0.031), gain at 1q32.1 (62%) positively associated with 6p “hot spot” gain (43%) (P = 0.033), and there was a trend for positive association between 1q and MYCN gain (P = 0.095). Cell lines had a higher frequency of MYCN amplification than primary tumors (29% versus 3%; P= 0.043). Novel high-level amplification of 1q32.1 in one primary tumor, confirmed by fluorescence in situ hybridization, strongly supports the presence of oncogene(s) in this region, possibly the mitotic kinesin, KIF14. Gene-specific quantitative multiplex polymerase chain reaction of candidate oncogenes at 1q32.1 (KIF14), 6p22 (E2F3 and DEK), and tumor suppressor genes at 16q22 (CDH11) and 17q21 (NGFR) showed the most common gene gains in RB to be KIF14 in cell lines (80%) and E2F3 in primary tumors (70%). The patterns of gain/loss were qualitatively different in 25 RB compared with 12 primary hepatocellular carcinoma and 12 breast cancer cell lines. Gene specific analysis of one bone marrow metastasis of RB, prechemotherapy and postchemotherapy, showed the typical genomic changes of RB pretreatment, which normalized after chemotherapy. © 2006 Wiley-Liss, Inc.

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