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Are there any more ovarian tumor suppressor genes? A new perspective using ultra high-resolution copy number and loss of heterozygosity analysis

Authors

  • Kylie L. Gorringe,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
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  • Manasa Ramakrishna,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
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  • Louise H. Williams,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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  • Anita Sridhar,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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  • Samantha E. Boyle,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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  • Jennifer L. Bearfoot,

    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
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  • Jason Li,

    1. Bioinformatics Core Facility, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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  • Michael S. Anglesio,

    1. Signal Transduction Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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  • Ian G. Campbell

    Corresponding author
    1. VBCRC Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
    • VBCRC Cancer Research Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, VIC 8006, Australia
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Abstract

Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number-neutral loss of heterozygosity (LOH). These alterations are assumed to represent the “second hit” of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high-resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of samples on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype-specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight samples), RB1 (five samples), and PTEN (three samples). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates. © 2009 Wiley-Liss, Inc.

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