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Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumours (internal and external) and malignant tumour types

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Abstract

Neurofibromatosis type 1 is a common familial cancer syndrome, affecting about 1 in every 4,000 individuals worldwide. We have carried out NF1 gene mutation analysis on DNA isolated from 25 tumours (dermal and plexiform neurofibromas, malignant peripheral nerve sheath tumour, MPNST), obtained at post-mortem from an NF1 patient. Macro and micro sequence alterations of the NF1 gene were studied by dHPLC, microsatellite, RFLP markers and multiplex ligation probe amplification (MLPA). The underlying germline mutation involves a deletion of exons 2 and 3. Of the 25 tumours studied from this patient, characterised somatic mutations were identified in 9 tumours, these were six small deletions (748del T, 2534–2557 del 24bp, 2843delA, 3047–3048 del GT, 4743del G, 7720–7721 delAA), an insertion 649 ins 73 bp, a non-sense mutation R1513X and a single splice site mutation, IVS4C-1 G>A, eight of these represent novel sequence changes in the gene. Evidence for loss of heterozygosity (LOH) was identified in DNA from 7 of the tumours. Each of the tumours analysed contained a different somatic NF1 mutation, indicating that each tumour is the result of an independent somatic event. The somatic mutation detection rate in this study is 64% (16/25), is one of the highest rates in genomic DNA reported so far in a single NF1 patient. Only 68 characterised NF1 somatic mutations have so far been reported and so our data will contribute to NF1 somatic mutational spectrum of the NF1 gene and will be important for understanding the molecular basis of NF1 tumorigenesis.

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Acknowledgements

We are grateful to Cancer Research UK, the Welsh Gene Park and NF Association for the financial support. We thank the patient and his family, especially his mother for their support and Dr Nick Thomas for reading the manuscript. We thank Drs Mark Rogers and Alex Murray for making arrangements for the biopsy.

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Authors and Affiliations

  1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

    Gill Spurlock, Siân Griffiths & Meena Upadhyaya

  2. Pathology Department, Gloucestershire Royal Hospital, Great Western Rd, Gloucester, GL1 3NN, UK

    Jeremy Uff

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  1. Gill Spurlock
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Correspondence to Meena Upadhyaya.

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Spurlock, G., Griffiths, S., Uff, J. et al. Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumours (internal and external) and malignant tumour types. Familial Cancer 6, 463–471 (2007). https://doi.org/10.1007/s10689-007-9149-5

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