Abstract
Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ∼80 kb to ∼8 Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation. Hum Mutat 32:78–90, 2011. © 2010 Wiley-Liss, Inc.
Highlights
One of the main challenges in the study of Neurofibromatosis type 1 (NF1, MIM] 162200) is to have the ability to predict the course of the disease
A high percentage of non-loss of heterozygosity (LOH) cells within neurofibromas can greatly hamper the detection of a loss of 1 copy of the NF1 gene using techniques such as multiplex ligation-dependent probe amplification (MLPA) or paralog ratio analysis (PRA)
We tested the limits of detection of MLPA and PRA techniques for correctly finding a deletion in the NF1 gene in the context of different proportions of non-LOH cells within neurofibromas
Summary
One of the main challenges in the study of Neurofibromatosis type 1 (NF1, MIM] 162200) is to have the ability to predict the course of the disease. Prognostic markers can only be found if we have a complete understanding of how the genetics and the environment influence the different traits that compose the NF1 phenotype One such trait is the development of dermal neurofibromas (dNFs) in multiple numbers, benign tumors of the peripheral nervous system. Two types of constitutional NF1 mutations have been found to influence neurofibroma number: Type-1 deletions (1.4-Mb deletions with breakpoints located within NF1-REPs a and c) seem to be associated with the early onset of a large number of dNFs [Kayes et al, 1994; Wu et al, 1995] and the c.2970-2972 delAAT mutation has been identified in patients with an absence of dNFs [Upadhyaya et al, 2007] These two types of constitutional mutations only account for a small percentage of NF1 patients. It has been observed that patients bearing the same germline mutation, even affected patients from the same family, can exhibit a very different number of dNFs [Ars et al, 2000; Carey et al, 1979], possible confounding factors, such as patient’s age, need to be analyzed more carefully
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