Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.
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Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. / Beert, Eline; Brems, Hilde; Daniëls, Bruno; Ivo, De Wever; Frank, Van Calenbergh; Schoenaers, Joseph; Debiec-Rychter, Maria; Gevaert, Olivier; Thomas, De Raedt; Annick, Van Den Bruel; de Ravel, Thomy; Cichowski, Karen; Kluwe, Lan; Mautner, Viktor Felix; Sciot, Raf; Legius, Eric.
In: GENE CHROMOSOME CANC, Vol. 50, No. 12, 12, 2011, p. 1021-1032.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.
AU - Beert, Eline
AU - Brems, Hilde
AU - Daniëls, Bruno
AU - Ivo, De Wever
AU - Frank, Van Calenbergh
AU - Schoenaers, Joseph
AU - Debiec-Rychter, Maria
AU - Gevaert, Olivier
AU - Thomas, De Raedt
AU - Annick, Van Den Bruel
AU - de Ravel, Thomy
AU - Cichowski, Karen
AU - Kluwe, Lan
AU - Mautner, Viktor Felix
AU - Sciot, Raf
AU - Legius, Eric
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Middle Aged
KW - Risk Factors
KW - Adolescent
KW - Young Adult
KW - Child
KW - Mutation
KW - Chromosome Aberrations
KW - Tumor Cells, Cultured
KW - Comparative Genomic Hybridization/methods
KW - Tumor Suppressor Protein p53/genetics
KW - Cyclin-Dependent Kinase Inhibitor p15/genetics
KW - Cyclin-Dependent Kinase Inhibitor p16/genetics
KW - DNA Copy Number Variations
KW - Genes, Neurofibromatosis 1
KW - Karyotyping/methods
KW - Nerve Sheath Neoplasms/genetics/pathology
KW - Neurofibroma/genetics/pathology
KW - Neurofibromatosis 1/genetics/pathology
KW - Precancerous Conditions/genetics/pathology
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Middle Aged
KW - Risk Factors
KW - Adolescent
KW - Young Adult
KW - Child
KW - Mutation
KW - Chromosome Aberrations
KW - Tumor Cells, Cultured
KW - Comparative Genomic Hybridization/methods
KW - Tumor Suppressor Protein p53/genetics
KW - Cyclin-Dependent Kinase Inhibitor p15/genetics
KW - Cyclin-Dependent Kinase Inhibitor p16/genetics
KW - DNA Copy Number Variations
KW - Genes, Neurofibromatosis 1
KW - Karyotyping/methods
KW - Nerve Sheath Neoplasms/genetics/pathology
KW - Neurofibroma/genetics/pathology
KW - Neurofibromatosis 1/genetics/pathology
KW - Precancerous Conditions/genetics/pathology
M3 - SCORING: Journal article
VL - 50
SP - 1021
EP - 1032
JO - GENE CHROMOSOME CANC
JF - GENE CHROMOSOME CANC
SN - 1045-2257
IS - 12
M1 - 12
ER -
