Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients

Authors

  • Ramprasath Venkatachalam,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Eugène T.P. Verwiel,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Eveline J. Kamping,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Eveline Hoenselaar,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Heike Görgens,

    1. Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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  • Hans K. Schackert,

    1. Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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  • J. Han J.M. van Krieken,

    1. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Marjolijn J.L. Ligtenberg,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
    2. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Nicoline Hoogerbrugge,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Ad Geurts van Kessel,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
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  • Roland P. Kuiper

    Corresponding author
    1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Centre for Oncology, Nijmegen, The Netherlands
    • Department of Human Genetics 855, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, Tel.: 31-24-3610868, Tel: +44 (0)114-226-5458, Fax: +44-114-271-7863
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  • Conflict of interest: The authors declare no conflict of interest.

Abstract

In the majority of colorectal cancers (CRCs) under clinical suspicion for a hereditary cause, the disease-causing genetic factors are still to be discovered. To identify such genetic factors we stringently selected a discovery cohort of 41 CRC index patients with microsatellite-stable tumors. All patients were below 40 years of age at diagnosis and/or exhibited an overt family history. We employed genome-wide copy number profiling using high-resolution SNP arrays on germline DNA, which resulted in the identification of novel copy number variants (CNVs) in six patients (15%) encompassing, among others, the cadherin gene CDH18, the bone morphogenetic protein antagonist family gene GREM1, and the breakpoint cluster region gene BCR. In addition, two genomic deletions were encountered encompassing two microRNA genes, hsa-mir-491/KIAA1797 and hsa-mir-646/AK309218. None of these CNVs has previously been reported in relation to CRC predisposition in humans, nor were they encountered in large control cohorts (>1,600 unaffected individuals). Since several of these newly identified candidate genes may be functionally linked to CRC development, our results illustrate the potential of this approach for the identification of novel candidate genes involved in CRC predisposition.

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