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

Eduard Serra, Susana Puig, David Otero, Antonia Gaona, Helena Kruyer, Elisabet Ars, Xavier Estivill, Conxi Lázaro

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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.

Original languageEnglish
Pages (from-to)512-519
Number of pages8
JournalAmerican Journal of Human Genetics
Volume61
Issue number3
DOIs
Publication statusPublished - Sep 1997

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Serra, E., Puig, S., Otero, D., Gaona, A., Kruyer, H., Ars, E., Estivill, X., & Lázaro, C. (1997). Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. American Journal of Human Genetics, 61(3), 512-519. https://doi.org/10.1086/515504