Abstract
A hallmark clinical feature of neurofibromatosis 1 (NF1) is multiple dermal neurofibromas, benign tumours that typically appear in early adolescence and increase in numbers throughout life. The pathogenesis of these tumours is not known. One domain of the NF1 gene product, neurofibromin, stimulates the intrinsic GTPase of Ras1–3, and inactivation of both NF1 alleles has been demonstrated in specific malignancies4–15. These observations support the contention that the NF1 gene product is a tumour suppressor that is involved in the Ras signal transduction pathway. Even though accumulating evidence demonstrates that NF1 acts as a tumour suppressor in some cells, mutations have not been identified in both NF1 alleles in dermal neurofibromas. Using standard techniques to analyse DNA extracted from benign neurofibromas, numerous investigators failed to identify loss of heterozygosity (LOH) in multiple tumours6–8,14–16. In contrast to these reports, Colman et al.17 demonstrated NF1 LOH of dermal neurofibromas derived from 2 of 5 NF1 patients, yet the constitutional NF1 mutations in these patients were not identified, and the extent of the somatic deletions beyond the NF1 locus were not established. In this study, we show that a dermal neurofibroma from an NF1 individual who has a constitutional deletion of the entire NF1 locus harbours a 4-bp deletion of NF1 exon 4b in the other allele. This is the first definitive identification of a somatic mutation which is limited to the NF1 locus in a benign neurofibroma from an NF1 individual in whom the constitutional NF1 mutation is known.
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References
Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).
Martin, G.A. et al. The GAP-related domain of the NF1 gene product interacts with ras p21. Cell 63, 843–849 (1990).
Xu, G. et al. The catalytic domain of the NF1 gene product stimulates ras GTPase and complements IRA mutants of S. Cerevisiae. Cell 63, 835–841 (1990).
Shannon, K. et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. New Engl. J. Med. 330, 597–601 (1994).
Xu, W. et al. Loss of NF1 alleles in pheochromocytomas from patients with type 1 neurofibromatosis. Genes Chromosom. & Cancer 4, 337–342 (1992).
Menon, A.G. et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc. Natl. Acad. Sci U.S.A 87, 5435–5439 (1990).
Skuse, G.R., Kosciolek, B.A. & Rowley, P.T. Loss of heterozygosity in malignancies in von Recklinghausen neurofibromatosis: The allele remaining in the tumor is derived from the affected parent. Am. J. Hum. Genet. 49, 600–607 (1990).
Glover, T.W. et al. Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. Genes Chrom. Cancer 3, 62–70 (1991).
Basu, T. et al. Aberrant regulation of RAS proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).
DeClue, J.E. et al. Abnormal regulation of mammalian p21 contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265–273 (1992).
Legius, E., Marchuk, D., Collins, F. & Glover, T. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nature Genet. 3, 122–126 (1993).
Reynolds, J. et al. Molecular characterization of a 17q11.2 translocation in a malignant schwannoma cell line. Hum. Genet. 90, 450–456 (1992).
Anderson, L. et al. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nature Genet. 3, 118–121 (1993).
Skuse, G.R., Kosciolek, B.A. & Rowley, P.T. Molecular genetic analysis of tumors in von Recklinghausen neurofibromatosis: Loss of heterozygosity for chromosome 17. Genes Chrom. Cancer 1, 36–41 (1989).
Shimizu, E. et al. Loss of heterozygosity on chromosome arm 17p in small cell lung carcinomas but not in neurofibromas, in a patient with von Recklinghausen neurofibromatosis. Cancer 71, 725–728 (1993).
Lothe, R. et al. Alterations at chromosome 17 loci in peripheral nerve sheath tumors. J. Neuropath. Exp. Neurol. 54, 65–73 (1995).
Colman, S.D., Williams, C.A. & Wallace, M.R. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nature Genet. 11, 90–92 (1995).
Kayes, L. et al. Deletions spanning the neurofibromatosis 1 gene: Identification and phenotype of five patients. Am. J. Hum. Genet. 54, 424–436 (1994).
Leppig, K. et al. The detection of contiguous gene deletions at the neurofibromatosis 1 locus with fluorescence in situ hybridization. Cytogenet. Cell Genet. 72, 95–98 (1996).
Marchuk, D. et al. A yeast artificial chromosome contig encompassing the type 1 neurofibromatosis gene. Genomics 13, 672–680 (1992).
Sawada, S. & Vlskochil, D. Detection of a germline mutation at the neurofibromatosis 1 locus. Jap. J. Dermatol. 105, 1187–1196 (1995).
Li, Y. et al. Genomic Organization of the neurofibromatosis 1 (NF1) locus. Genomics 25, 9–18 (1995).
Marchuk, D.A. et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11, 931–40 (1991).
Bollag, G. et al. Loss of NF1 results in activation of the ras signalling pathway and leads to aberrant growth in haematopoietic cells. Nafure Genet. 12, 144–148, (1996).
Largaespada, D., Brannan, C., Jenkins, N. & Copeland, N. Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia . Nature Genet. 12, 137–143 (1996).
Fialkow, P.J., Sagebiel, R.W., Gartler, S.M. & Rimoin, D.I. Multiple cell origin of hereditary neurofibromas. New Engl. J. Med. 284, 298–300 (1971).
Skuse, G., Kosciolek, B. & Rowley, P. The neurofibroma in von Recklinghausen neurofibromatosis has a unicellular origin. Am. J. Hum. Genet. 49, 600–607 (1991).
Enzinger, F. & Weiss, S. Benign tumors of peripheral nerves. in Soft tissue Tumors. (eds Gay, S. & Gery, L) 821–885 (Mosby-Yearbook, St. Louis, 1988).
Samowitz, W., Slattery, M.L. & Kerber, R.A. Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer. Gastroent. 109, 1765–1771 (1995).
Sambrook, J., Fritsch, E. & Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd edn. (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).
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Sawada, S., Florell, S., Purandare, S. et al. Identification of NF1 mutations in both alleles of a dermal neurofibroma. Nat Genet 14, 110–112 (1996). https://doi.org/10.1038/ng0996-110
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DOI: https://doi.org/10.1038/ng0996-110
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