title: Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.
abstract: Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. gutmannd@neuro.wustl.edu
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Hussain
authors.forename: John W
authors.initials: JW
authors.lastname: Wallis
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Fulton
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.forename: Ryan
authors.initials: R
authors.lastname: Demeter
authors.forename: Todd
authors.initials: T
authors.lastname: Wylie
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
mesh_terms: D000293:Adolescent; D000483:Alleles; D001254:Astrocytoma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002648:Child; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D016514:Genes, Neurofibromatosis 1; D055106:Genome-Wide Association Study; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D015203:Reproducibility of Results; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D025542:Neurofibromin 1