Original articlesAllelic Loss of the NF1 Gene in NF1-Associated Plexiform Neurofibromas
Introduction
Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with an incidence of one in 4000. This neurocutaneous disorder is associated with a variety of benign and malignant lesions (café-au-lait spots, neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, and pilocytic astrocytomas) 1, 2, 3. Plexiform neurofibromas—a variant of neurofibroma—are diagnosed in about 30% of patients [4]. A plexiform neurofibroma frequently originates from subcutaneous or visceral peripheral nerves and may cause a fusiform appearance in the affected nerve. Plexiform neurofibromas have the potential for malignant progression into malignant peripheral nerve sheath tumors; therefore, they have a position between benign and malignant NF1-related tumors. Plexiform neurofibromas are located in the chest, abdomen, or pelvis, and are commonly detected as a paraspinal mass that involves multiple spinal levels. They may also appear as anterior mediastinal masses, sciatic nerve lesions with pelvic extension, perirectal plexiform, and uterine tumors, all leading to severe clinical complications [5]. In contrast, dermal neurofibromas in NF1 are characterized by their superficial location and occurrence in large numbers. These tumors originate from terminal nerve branches in the skin and are not associated with major peripheral nerve trunks.
NF1 is caused by genetic alterations of the NF1 gene located on 17q11.2 6, 7, 8. This gene encompasses 335 kb of genomic DNA and consists of 60 exons which give rise to an 11–13-kb transcript. The product of the NF1 gene, neurofibromin, is considered a tumor suppressor in the sense that inactivation of both NF1 alleles would lead to tumorigenesis [9]. Allelic loss of chromosome 17, including the NF1 locus, has been found in NF1-related malignant tumors 10, 11. Recently, using intragenic markers in addition to conventional flanking markers, allelic loss of the NF1 gene was found in eight of 22 [12] and in 15 of 60 [13] benign neurofibromas. Furthermore, in one dermal neurofibroma [14] and one plexiform neurofibroma [15], genetic alterations have been identified on both alleles of the NF1 gene. These results supported the hypothesis that NF1 is a tumor suppressor gene. Rasmussen et al. [16] has recently reported NF1 allelic loss in seven of 14 plexiform neurofibromas at the Neurofibromatosis Symposium; however, the detailed result has not yet been published.
In this study, we examined NF1 allelic loss in 14 clinically and neuroradiologically ascertained plexiform neurofibromas removed from 10 NF1 patients. Using temperature gradient gel electrophoresis (TGGE), we also examined these tumors for mutations in the TP53 gene by screening exons 5–8 of the gene.
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Materials and methods
NF1-patients were diagnosed according to standard criteria. The protocol was approved by the institutional review board, and all participants provided informed consent. Eight patients were examined in our NF center. They underwent magnetic resonance imaging (MRI) of the brain, ultrasound of abdominal organs, ophthalmological investigation, and neurological examinations. Another two patients (x1 and 241) were examined at outside clinics. Plexiform neurofibromas were diagnosed on the following
Results
Clinical data of the 10 patients were summarized in Table 1. All 14 plexiform neurofibromas from 10 NF1 patients were ascertained through macroscopic diagnosis and radiological examination. Twelve of these tumors were removed from the facial and neck area, the other two were from the lower leg (Table 1). In four patients (x1, 293, 290, and 279), two tumors were removed from each patient at an interval of 1–2 years. The second tumors stem from the same or overlapping region of corresponding
Discussion
By examining 14 plexiform neurofibromas from 10 patients, we detected LOH of intragenic NF1 markers in eight tumors from five patients, and suspected LOH in an additional tumor from another patient. In four patients, two tumors were removed from each patient from the same or overlapping region. The second tumor may therefore be recurrence of the corresponding previous tumor in each case. Genotype regarding LOH of the NF1 markers remained the same in the first and the second tumors from each
Acknowledgements
We thank K. Platzek and H. Meissner for their assistance, and Dr. M.Westphal for his support. This study is supported by Wilhelm-Sander-Stiftung 93.052.2, by Deutsche Krebshilfe 70-1947-Ma I, and in part by Hamburger Stiftung zur Förderung der Krebskämpfung 127, 130, 144.
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