Abstract
Patients with NF1 microdeletion develop more neurofibromas at a younger age, and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). We postulated that the increased risk of malignancy could be due to inactivation, in addition to NF1, of a second tumor suppressor gene located in the typical 1.4-Mb microdeletion found in most of the microdeleted patients. We investigated the expression of NF1, the other 16 protein-coding genes and the 2 microRNAs located in the 1.4-Mb microdeletion by means of real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) in a large series of human dermal and plexiform neurofibromas and MPNSTs. Five genes were significantly upregulated: OMG and SUZ12 in plexiform neurofibromas and ATAD5, EVI2A and C17orf79 in MPNSTs. More interestingly, two genes were significantly downregulated (RNF135 and CENTA2) in tumor Schwann cells from MPNST biopsies and in MPNST cell lines. This study points to the involvement of several genes (particularly RNF135 and CENTA2) in the increased risk of malignancy observed in NF1-microdeleted patients.
Highlights
Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder affecting 1 in 3,000 individuals worldwide [1]
NF1 Mutation Analysis Germline NF1 mutations and loss of heterozygosity assessment in plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) of the study NF1 patients are summarized in Supplemental Table 3
We examined the expression of NF1, the other 16 protein-coding genes and the 2 microRNA genes located within the 1.4-Mb deletion by means of real-time quantitative reversetranscription polymerase chain reaction (RT-PCR) in a large series of dermal and plexiform neurofibromas and MPNSTs
Summary
Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder affecting 1 in 3,000 individuals worldwide [1]. Main clinical characteristics of NF1 include café au lait spots (CALS), Lish nodules, freckling and neurofibromas. These patients are at an increased risk of both benign and malignant tumors, and NF1 is classified as a tumor predisposition syndrome. In contrast to dermal neurofibromas, plexiform neurofibromas can progress to malignant peripheral nerve sheath tumors (MPNSTs) in about 10% of patients with NF1 [5]. MPNSTs are resistant to conventional therapies, and their deepseated position and locally invasive growth hinder complete surgical resection. Both neurofibromas and MPNSTs are heterogeneous tumors mainly composed of Schwann cells (60–80%), together with fibroblasts, mast cells and other cell types. Schwann cells are considered to be the pathogenic cell type of these two tumor types
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