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High-resolution array-CGH profiling of germline and tumor-specific copy number alterations on chromosome 22 in patients affected with schwannomas

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Abstract

Schwannomas may develop sporadically or in association with NF2 and schwannomatosis. The fundamental aberration in schwannomas is the bi-allelic inactivation of the NF2 gene. However, clinical and molecular data suggest that these tumors share a common pathogenetic mechanism related to as yet undefined 22q-loci. Linkage studies in schwannomatosis, a condition related to NF2, have defined a candidate 22q-locus and excluded the NF2 gene as the causative germline mutation. Thus, analysis of aberrations in schwannomas may lead to the identification of putative gene(s) involved in the development of schwannoma/schwannomatosis. We profiled a series of 88 schwannomas and constitutional DNA using a tiling path chromosome 22 array. Array-CGH is a suitable method for high-resolution discrimination between germline and tumor-specific aberrations. Previously reported frequencies of 22q-associated deletions in schwannomas display large discrepancies, ranging from 30% to 80%. We detected heterozygous deletions in 53% of schwannomas and the predominant pattern was monosomy 22. In addition, three tumors displayed terminal deletions and four harbored overlapping interstitial deletions of various sizes encompassing the NF2 gene. When profiling constitutional DNA, we identified eight loci that were affected by copy number variation (CNV). Some of the identified CNVs may not be phenotypically neutral and the possible role of these CNVs in the pathogenesis of schwannomas should be studied further. We observed a correlation between the breakpoint position, present in tumor and/or constitutional DNA and the location of segmental duplications. This association implicates these unstable regions in rearrangements occurring both in meiosis and mitosis.

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Abbreviations

ANILFR:

Average Normalized Inter-Locus Fluorescence Ratio

Array-CGH:

Array-based comparative genomic hybridization

CGH:

Comparative Genomic Hybridization

CNV:

Copy Number Variation

CCNV:

Common Copy Number Variation

RCNV:

Rare Copy Number Variation

IGLV :

Immunoglobulin Lambda Variable

LCRs:

Low Copy Repeats

NF2:

Neurofibromatosis type 2

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Acknowledgements

This work was supported by grants from the US Army Medical Research and Materiel Command (award no. W81XWH-04-1-0269), the Swedish Cancer Foundation, the Swedish Research Council and Uppsala University to JPD. CDB is supported by a fellowship from the Department of Education, Universities and Research of the Basque Government.

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Authors and Affiliations

  1. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden

    Teresita Díaz de Ståhl, Caisa M. Hansson, Cecilia de Bustos, Kiran K. Mantripragada, Arkadiusz Piotrowski, Magdalena Benetkiewicz, Caroline Jarbo & Jan P. Dumanski

  2. Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden

    Leif Wiklund

  3. Department of Neurology, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Leif Wiklund

  4. Department of Neurosurgery, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden

    Tiit Mathiesen

  5. Department of Neurosurgery, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Gunnar Nyberg

  6. Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK

    V. Peter Collins & Koichi Ichimura

  7. Academic Unit of Medical Genetics and Regional Genetics Service, St Mary’s Hospital, Manchester, M13 0JH, UK

    D. Gareth Evans

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  1. Teresita Díaz de Ståhl
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  2. Caisa M. Hansson
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  6. Magdalena Benetkiewicz
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  7. Caroline Jarbo
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  10. Gunnar Nyberg
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  11. V. Peter Collins
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  12. D. Gareth Evans
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Correspondence to Jan P. Dumanski.

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Díaz de Ståhl, T., Hansson, C.M., Bustos, C.d. et al. High-resolution array-CGH profiling of germline and tumor-specific copy number alterations on chromosome 22 in patients affected with schwannomas. Hum Genet 118, 35–44 (2005). https://doi.org/10.1007/s00439-005-0002-3

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