title: Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.
abstract: Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.
authors: Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.
authors: Eline
authors: E
authors: Beert
authors: Hilde
authors: H
authors: Brems
authors: Bruno
authors: B
authors: Daniëls
authors: Ivo
authors: I
authors: De Wever
authors: Frank
authors: F
authors: Van Calenbergh
authors: Joseph
authors: J
authors: Schoenaers
authors: Maria
authors: M
authors: Debiec-Rychter
authors: Olivier
authors: O
authors: Gevaert
authors: Thomas
authors: T
authors: De Raedt
authors: Annick
authors: A
authors: Van Den Bruel
authors: Thomy
authors: T
authors: de Ravel
authors: Karen
authors: K
authors: Cichowski
authors: Lan
authors: L
authors: Kluwe
authors: Victor
authors: V
authors: Mautner
authors: Raf
authors: R
authors: Sciot
authors: Eric
authors: E
authors: Legius
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization / Q000379:methods; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D056915:DNA Copy Number Variations; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D007621:Karyotyping / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology*; D009455:Neurofibroma / Q000235:genetics / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D012307:Risk Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53