Analysis of Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1 Patients

Introduction Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder occuring in 1 out of 3500 living newborns. The disease is caused by heterozygous mutations of the NF1 gene, located on chromosome 17q11.2. The NF1 gene encodes the tumor suppressor neurofibromin, a negative regulator of the RAS/MAPK pathway. In approximately 95% of patients, the heterozygous mutation is intragenic. The remaining 5% of patients are carrier of a microdeletion, mostly the type 1 deletion, in which apart from the NF1 gene, 14 additional protein coding genes are located.

Clinically, NF1 patients have café-au-lait maculae, freckling, Lisch nodules and neurofibromas. Also cognitive problems, bone lesions and optic pathway gliomas are common in these patients.

Neurofibromas are benign neoplasms of the peripheral nerve sheath, which appear everywhere on the body of almost every NF1 patient. Neurofibromas are composed of different cell types like Schwann cells, fibroblasts, mast cells and perineurial cells. If in Schwann cells of NF1 patients the wild-type NF1 allele is inactivated in a heterozygous microenvironment, a neurofibroma will be formed. There are 3 types of neurofibromas: cutaneous, subcutaneous and plexiform. Cutaneous and subcutaneous neurofibromas appear during adolescence as isolated nodules in or under the skin, respectively. Plexiform neurofibromas are congenital and can spread along a large segment of a peripheral nerve. NF1 microdeletion patients have in general more neurofibromas and they appear at a younger age.

Every NF1 patient has a life time risk of 8 to 13% to develop a malignant peripheral nerve sheath tumor (MPNST) out of a pre-existing (plexiform) neurofibroma. This risk is even twice as high for NF1 microdeletion patients compared to patients with an intragenic mutation. MPNSTs are difficult to diagnose in early phase because of the large number of tumors and diverse locations. These tumors infiltrate easily in surrounding tissue and frequently give rise to metastases. At this moment, the only available treatment is surgical removal of these MPNSTs. Complete resection is often difficult due to the size of the tumors and the location on important nerves. The five-year survival of patients with MPNSTs is less than 25%.

Research protocol All NF1 patients are linked to the UZ Leuven. Their follow-up is done by Prof. Dr. Eric Legius. When the patient is suspected of having a MPNST, the patient is referred to the surgeon of the clinical oncology department, respectively. Also neurofibromas are removed when they are causing problems for the patient. As part of the different tumor care programs in our hospital, a tumor piece is sent from pathology to the centre for human genetics for routine genetical analysis, like karyotyping. In the lab for neurofibromatosis research, the rest material is frozen as tumor pieces and as dissociated cells for research purposes. The samples are stored in a database system that is accessible only for the neurofibromatosis research group. In cooperation with the group of Victor Mautner and Karen Cichowski, the tumor database was further completed with NF1 tumor material and cell lines. The latter samples were coded and could be used as part of our collaboration.