title: Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non-microdeletion patients.
abstract: Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome characterized by the presence of multiple benign neurofibromas. In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes. We studied the frequency of loss of heterozygosity (LOH) in the NF1 region as a mechanism of somatic NF1 inactivation in neurofibromas from NF1 patients with and without a microdeletion. There was a statistically significant difference between these two patient groups in the proportion of neurofibromas with LOH. None of the 40 neurofibromas from six different NF1 microdeletion patients showed LOH, whereas LOH was observed in 6/28 neurofibromas from five patients with an intragenic NF1 mutation (P = 0.0034, Fisher's exact). LOH of the NF1 microdeletion region in NF1 microdeletion patients would de facto lead to a nullizygous state of the genes located in the deletion region and might be lethal. The mechanisms leading to LOH were further analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal microdeletion was found; in three, a mitotic recombination was responsible for the observed LOH; and in one, a chromosome loss with reduplication was present. These data show an important difference in the mechanisms of second hit formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor syndrome in which the type of germline mutation influences the type of second hit in the tumors.
authors.affiliation: Center for Human Genetics, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Raedt
authors.forename: Ophélia
authors.initials: O
authors.lastname: Maertens
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chmara
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.forename: Ine
authors.initials: I
authors.lastname: Heyns
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Sofie
authors.initials: S
authors.lastname: De Schepper
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: Joris Robert
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D000483:Alleles; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D017353:Gene Deletion; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D009455:Neurofibroma / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004273:DNA, Neoplasm; D025542:Neurofibromin 1