Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1997 Sep;61(3):512–519. doi: 10.1086/515504

Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.

E Serra 1, S Puig 1, D Otero 1, A Gaona 1, H Kruyer 1, E Ars 1, X Estivill 1, C Lázaro 1
PMCID: PMC1715958  PMID: 9326316

Abstract

Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.

Full text

PDF
512

Images in this article

515Figure 2
on p.515

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen L. B., Fountain J. W., Gutmann D. H., Tarlé S. A., Glover T. W., Dracopoli N. C., Housman D. E., Collins F. S. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nat Genet. 1993 Feb;3(2):118–121. doi: 10.1038/ng0293-118. [DOI] [PubMed] [Google Scholar]
  2. Ballester R., Marchuk D., Boguski M., Saulino A., Letcher R., Wigler M., Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851–859. doi: 10.1016/0092-8674(90)90151-4. [DOI] [PubMed] [Google Scholar]
  3. Cawthon R. M., Weiss R., Xu G. F., Viskochil D., Culver M., Stevens J., Robertson M., Dunn D., Gesteland R., O'Connell P. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193–201. doi: 10.1016/0092-8674(90)90253-b. [DOI] [PubMed] [Google Scholar]
  4. Colman S. D., Williams C. A., Wallace M. R. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet. 1995 Sep;11(1):90–92. doi: 10.1038/ng0995-90. [DOI] [PubMed] [Google Scholar]
  5. De Vitis L. R., Tedde A., Vitelli F., Ammannati F., Mennonna P., Bigozzi U., Montali E., Papi L. Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic meningiomas. Hum Genet. 1996 May;97(5):632–637. doi: 10.1007/BF02281874. [DOI] [PubMed] [Google Scholar]
  6. Easton D. F., Ponder M. A., Huson S. M., Ponder B. A. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305–313. [PMC free article] [PubMed] [Google Scholar]
  7. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  8. Friedman T. B., Liang Y., Weber J. L., Hinnant J. T., Barber T. D., Winata S., Arhya I. N., Asher J. H., Jr A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat Genet. 1995 Jan;9(1):86–91. doi: 10.1038/ng0195-86. [DOI] [PubMed] [Google Scholar]
  9. Glover T. W., Stein C. K., Legius E., Andersen L. B., Brereton A., Johnson S. Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. Genes Chromosomes Cancer. 1991 Jan;3(1):62–70. doi: 10.1002/gcc.2870030111. [DOI] [PubMed] [Google Scholar]
  10. Ichii S., Horii A., Nakatsuru S., Furuyama J., Utsunomiya J., Nakamura Y. Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Hum Mol Genet. 1992 Sep;1(6):387–390. doi: 10.1093/hmg/1.6.387. [DOI] [PubMed] [Google Scholar]
  11. Kamata Y. Study on the ultrastructure and acetylcholinesterase activity in von Recklinghausen's neurofibromatosis. Acta Pathol Jpn. 1978 May;28(3):393–410. doi: 10.1111/j.1440-1827.1978.tb01264.x. [DOI] [PubMed] [Google Scholar]
  12. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Legius E., Marchuk D. A., Collins F. S., Glover T. W. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 1993 Feb;3(2):122–126. doi: 10.1038/ng0293-122. [DOI] [PubMed] [Google Scholar]
  14. Levanat S., Gorlin R. J., Fallet S., Johnson D. R., Fantasia J. E., Bale A. E. A two-hit model for developmental defects in Gorlin syndrome. Nat Genet. 1996 Jan;12(1):85–87. doi: 10.1038/ng0196-85. [DOI] [PubMed] [Google Scholar]
  15. Li Y., Bollag G., Clark R., Stevens J., Conroy L., Fults D., Ward K., Friedman E., Samowitz W., Robertson M. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell. 1992 Apr 17;69(2):275–281. doi: 10.1016/0092-8674(92)90408-5. [DOI] [PubMed] [Google Scholar]
  16. Li Y., O'Connell P., Breidenbach H. H., Cawthon R., Stevens J., Xu G., Neil S., Robertson M., White R., Viskochil D. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics. 1995 Jan 1;25(1):9–18. doi: 10.1016/0888-7543(95)80104-t. [DOI] [PubMed] [Google Scholar]
  17. Lothe R. A., Slettan A., Saeter G., Brøgger A., Børresen A. L., Nesland J. M. Alterations at chromosome 17 loci in peripheral nerve sheath tumors. J Neuropathol Exp Neurol. 1995 Jan;54(1):65–73. doi: 10.1097/00005072-199501000-00008. [DOI] [PubMed] [Google Scholar]
  18. Lázaro C., Gaona A., Ainsworth P., Tenconi R., Vidaud D., Kruyer H., Ars E., Volpini V., Estivill X. Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet. 1996 Dec;98(6):696–699. doi: 10.1007/s004390050287. [DOI] [PubMed] [Google Scholar]
  19. Martin G. A., Viskochil D., Bollag G., McCabe P. C., Crosier W. J., Haubruck H., Conroy L., Clark R., O'Connell P., Cawthon R. M. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990 Nov 16;63(4):843–849. doi: 10.1016/0092-8674(90)90150-d. [DOI] [PubMed] [Google Scholar]
  20. Menon A. G., Anderson K. M., Riccardi V. M., Chung R. Y., Whaley J. M., Yandell D. W., Farmer G. E., Freiman R. N., Lee J. K., Li F. P. 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. 1990 Jul;87(14):5435–5439. doi: 10.1073/pnas.87.14.5435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ottini L., Esposito D. L., Richetta A., Carlesimo M., Palmirotta R., Verí M. C., Battista P., Frati L., Caramia F. G., Calvieri S. Alterations of microsatellites in neurofibromas of von Recklinghausen's disease. Cancer Res. 1995 Dec 1;55(23):5677–5680. [PubMed] [Google Scholar]
  23. Rahman N., Arbour L., Tonin P., Renshaw J., Pelletier J., Baruchel S., Pritchard-Jones K., Stratton M. R., Narod S. A. Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Nat Genet. 1996 Aug;13(4):461–463. doi: 10.1038/ng0896-461. [DOI] [PubMed] [Google Scholar]
  24. Rogers G. R., Rizzo W. B., Zlotogorski A., Hashem N., Lee M., Compton J. G., Bale S. J. Genetic homogeneity in Sjögren-Larsson syndrome: linkage to chromosome 17p in families of different non-Swedish ethnic origins. Am J Hum Genet. 1995 Nov;57(5):1123–1129. [PMC free article] [PubMed] [Google Scholar]
  25. Rosenbaum T., Boissy Y. L., Kombrinck K., Brannan C. I., Jenkins N. A., Copeland N. G., Ratner N. Neurofibromin-deficient fibroblasts fail to form perineurium in vitro. Development. 1995 Nov;121(11):3583–3592. doi: 10.1242/dev.121.11.3583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sawada S., Florell S., Purandare S. M., Ota M., Stephens K., Viskochil D. Identification of NF1 mutations in both alleles of a dermal neurofibroma. Nat Genet. 1996 Sep;14(1):110–112. doi: 10.1038/ng0996-110. [DOI] [PubMed] [Google Scholar]
  27. Shannon K. M., O'Connell P., Martin G. A., Paderanga D., Olson K., Dinndorf P., McCormick F. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med. 1994 Mar 3;330(9):597–601. doi: 10.1056/NEJM199403033300903. [DOI] [PubMed] [Google Scholar]
  28. Shen M. H., Harper P. S., Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet. 1996 Jan;33(1):2–17. doi: 10.1136/jmg.33.1.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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 Chromosomes Cancer. 1989 Sep;1(1):36–41. doi: 10.1002/gcc.2870010107. [DOI] [PubMed] [Google Scholar]
  30. Stark M., Assum G., Krone W. Single-cell PCR performed with neurofibroma Schwann cells reveals the presence of both alleles of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1995 Nov;96(5):619–623. doi: 10.1007/BF00197423. [DOI] [PubMed] [Google Scholar]
  31. Stefansson K., Wollmann R., Jerkovic M. S-100 protein in soft-tissue tumors derived from Schwann cells and melanocytes. Am J Pathol. 1982 Feb;106(2):261–268. [PMC free article] [PubMed] [Google Scholar]
  32. The I., Murthy A. E., Hannigan G. E., Jacoby L. B., Menon A. G., Gusella J. F., Bernards A. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat Genet. 1993 Jan;3(1):62–66. doi: 10.1038/ng0193-62. [DOI] [PubMed] [Google Scholar]
  33. Upadhyaya M., Shaw D. J., Harper P. S. Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene. Hum Mutat. 1994;4(2):83–101. doi: 10.1002/humu.1380040202. [DOI] [PubMed] [Google Scholar]
  34. Viskochil D., Buchberg A. M., Xu G., Cawthon R. M., Stevens J., Wolff R. K., Culver M., Carey J. C., Copeland N. G., Jenkins N. A. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul 13;62(1):187–192. doi: 10.1016/0092-8674(90)90252-a. [DOI] [PubMed] [Google Scholar]
  35. Waggener J. D. Ultrastructure of benign peripheral nerve sheath tumors. Cancer. 1966 May;19(5):699–709. doi: 10.1002/1097-0142(196605)19:5<699::aid-cncr2820190516>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  36. Wallace M. R., Marchuk D. A., Andersen L. B., Letcher R., Odeh H. M., Saulino A. M., Fountain J. W., Brereton A., Nicholson J., Mitchell A. L. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181–186. doi: 10.1126/science.2134734. [DOI] [PubMed] [Google Scholar]
  37. Wu Q., Chen M., Buchwald M., Phillips R. A. A simple, rapid method for isolation of high quality genomic DNA from animal tissues. Nucleic Acids Res. 1995 Dec 25;23(24):5087–5088. doi: 10.1093/nar/23.24.5087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Xu G. F., Lin B., Tanaka K., Dunn D., Wood D., Gesteland R., White R., Weiss R., Tamanoi F. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990 Nov 16;63(4):835–841. doi: 10.1016/0092-8674(90)90149-9. [DOI] [PubMed] [Google Scholar]
  39. Xu G. F., O'Connell P., Viskochil D., Cawthon R., Robertson M., Culver M., Dunn D., Stevens J., Gesteland R., White R. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990 Aug 10;62(3):599–608. doi: 10.1016/0092-8674(90)90024-9. [DOI] [PubMed] [Google Scholar]
  40. Xu W., Mulligan L. M., Ponder M. A., Liu L., Smith B. A., Mathew C. G., Ponder B. A. Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis. Genes Chromosomes Cancer. 1992 Jun;4(4):337–342. doi: 10.1002/gcc.2870040411. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy