TY  - JOUR
A1  - Gutmann, David H.
A1  - McLellan, Michael D.
A1  - Hussain, Ibrahim
A1  - Wallis, John W.
A1  - Fulton, Lucinda L.
A1  - Fulton, Robert S.
A1  - Magrini, Vincent
A1  - Demeter, Ryan
A1  - Wylie, Todd
A1  - Kandoth, Cyriac
A1  - Leonard, Jeffrey R.
A1  - Guha, Abhijit
A1  - Miller, Christopher A.
A1  - Ding, Li
A1  - Mardis, Elaine R.
T1  - Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma
Y1  - 2013/03/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 431 
EP  - 439 
DO  - 10.1101/gr.142604.112 
VL  - 23 
IS  - 3 
UR  - http://genome.cshlp.org/content/23/3/431.abstract 
N2  - 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. 
ER  -