NDLI: Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma

Content Provider	PubMed Central
Author	Gutmann, David H. Mclellan, Michael D. Hussain, Ibrahim Wallis, John W. Fulton, Lucinda L. Fulton, Robert S. Magrini, Vincent Demeter, Ryan Wylie, Todd Kandoth, Cyriac Leonard, Jeffrey R. Guha, Abhijit Miller, Christopher A. Ding, Li Mardis, Elaine R.
Copyright Year	2013
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.
Related Links	http://dx.doi.org/10.1101/gr.142604.112
Ending Page	439
Page Count	9
Starting Page	431
File Format	PDF
ISSN	10889051
e-ISSN	15495469
Journal	Genome Research
Issue Number	3
Volume Number	23
Language	English
Publisher	Cold Spring Harbor Laboratory Press
Publisher Date	2013-03-01
Access Restriction	Open
Rights Holder	Cold Spring Harbor Laboratory Press
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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