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No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients

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Abstract

Neurofibromatosis type 1 (NF1) is a common monogenic disorder whereby affected individuals are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs, occurring in ~15 to 20 % of cases). So far, no definite genotype–phenotype correlation determining NF1 patients at risk for tumor formation has been described, although enrichment for mutations in the 5′ region of the NF1 gene in OPG patients has been suggested. We used whole exome sequencing, targeted sequencing, and copy number analysis to screen 77 unrelated NF1 patients with (n = 41) or without (n = 36; age ≥10 years) optic pathway glioma for germline NF1 alterations. We identified germline NF1 mutations in 69 of 77 patients (90 %), but no genotype–phenotype correlation was observed. Our data using a larger patient cohort did not confirm the previously reported clustering of mutations in the 5′ region of the NF1 gene in patients with OPG. Thus, NF1 mutation location should not currently be used as a clinical criterion to assess the risk of developing OPGs.

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Acknowledgments

We thank Laura Sieber, Linda Linke, Andrea Wittmann and the German Cancer Research Center Genomics and Proteomics Core Facility for technical support and sequencing services, and Barbara Hutter for analytical support. This work was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (DKH, #109252) and the German Federal Ministry of Education and Research (BMBF, #01KU1201A), and by the Bundesverband Neurofibromatose e.V., Germany. S.M.W. received funding through an SNSF early postdoc mobility fellowship (P2ELP3_155365) and an EMBO long-term fellowship (ALTF 755-2014).

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Authors and Affiliations

  1. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Sonja Hutter, Stefan M. Pfister & David T. W. Jones

  2. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Rosario M. Piro & Peter Lichter

  3. German Cancer Consortium (DKTK) Core Center Heidelberg, Heidelberg, Germany

    Rosario M. Piro, Olaf Witt, Peter Lichter, Stefan M. Pfister & David T. W. Jones

  4. Institute of Computer Science, Freie Universität Berlin, Berlin, Germany

    Rosario M. Piro

  5. Institute of Medical Genetics and Human Genetics, Charité University Hospital, Berlin, Germany

    Rosario M. Piro

  6. European Molecular Biology Laboratory (EMBL), Genome Biology Research Unit, Heidelberg, Germany

    Sebastian M. Waszak & Jan O. Korbel

  7. Institute of Human Genetics, University of Ulm, Ulm, Germany

    Hildegard Kehrer-Sawatzki

  8. Department of Oral and Cranio-Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Reinhard E. Friedrich

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

    Alvaro Lassaletta & Uri Tabori

  10. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Olaf Witt

  11. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany

    Olaf Witt & Stefan M. Pfister

  12. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Olaf Witt & Stefan M. Pfister

  13. Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany

    Martin U. Schuhmann

  14. Centre for Neurofibromatosis, Centre for Rare Diseases Tübingen, Tübingen, Germany

    Martin U. Schuhmann

  15. German Cancer Consortium (DKTK) Partner Site Tübingen, Tübingen, Germany

    Martin U. Schuhmann

  16. Department of Neurology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Victor F. Mautner

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  1. Sonja Hutter
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  14. David T. W. Jones
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Corresponding authors

Correspondence to Victor F. Mautner or David T. W. Jones.

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V. F. Mautner and T. W. Jones are co-senior authors.

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Hutter, S., Piro, R.M., Waszak, S.M. et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet 135, 469–475 (2016). https://doi.org/10.1007/s00439-016-1646-x

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  • DOI: https://doi.org/10.1007/s00439-016-1646-x

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