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High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor

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Abstract

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.

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Acknowledgments

The authors thank Dr. Sulagna Saitta for her helpful and informative discussions. We would also like to acknowledge Dr. Eric Rappaport, Elizabeth Geiger and Madhavi Vaddi for their technical assistance. Supported by grants from the National Institutes of Health CA46274, CA98543 (J.A.B.) and GM64725 (T.H.S.). Eric Jackson receives grant support from the Neurosurgery Research and Education Foundation.

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Authors and Affiliations

  1. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Eric M. Jackson

  2. Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Tamim H. Shaikh, Luanne M. Wainwright, Fan Zhang & Jaclyn A. Biegel

  3. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Tamim H. Shaikh & Jaclyn A. Biegel

  4. The Preston Robert Tisch Brain Tumor Center and the Departments of Pediatrics and Surgery, Duke University Medical Center, Durham, NC, USA

    Sridharan Gururangan

  5. Division of Dysmorphology and Genetics, Rady Children’s Hospital, San Diego, CA, USA

    Marilyn C. Jones

  6. Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    David Malkin

  7. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Sarah M. Nikkel

  8. Department of Pathology, Loma Linda University Medical Center, Loma Linda, CA, USA

    Craig W. Zuppan

  9. The Children’s Hospital of Philadelphia, Abramson Research Building, Room 1002, 3615 Civic Center Boulevard, Philadelphia, PA, 19104, USA

    Jaclyn A. Biegel

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  1. Eric M. Jackson
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  10. Jaclyn A. Biegel
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Correspondence to Jaclyn A. Biegel.

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Jackson, E.M., Shaikh, T.H., Gururangan, S. et al. High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor. Hum Genet 122, 117–127 (2007). https://doi.org/10.1007/s00439-007-0386-3

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  • DOI: https://doi.org/10.1007/s00439-007-0386-3

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