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Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors
Author(s) -
Beert Eline,
Brems Hilde,
Daniëls Bruno,
De Wever Ivo,
Van Calenbergh Frank,
Schoenaers Joseph,
DebiecRychter Maria,
Gevaert Olivier,
De Raedt Thomas,
Van Den Bruel Annick,
de Ravel Thomy,
Cichowski Karen,
Kluwe Lan,
Mautner Victor,
Sciot Raf,
Legius Eric
Publication year - 2011
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20921
Subject(s) - cdkn2a , neurofibromatosis , neurofibroma , comparative genomic hybridization , plexiform neurofibroma , pathology , malignant peripheral nerve sheath tumor , neurofibromatosis type i , medicine , biology , cancer , chromosome , gene , genetics
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. © 2011 Wiley Periodicals, Inc.