神经纤维蛋白1
生物
杂合子丢失
移码突变
种系突变
体细胞
癌症研究
生殖系
毛细胞星形细胞瘤
神经纤维瘤病
纤维神经瘤
星形细胞瘤
遗传学
抑癌基因
突变
癌变
等位基因
胶质瘤
癌症
基因
作者
David H. Gutmann,Michael D. McLellan,Ibrahim Hussain,John W. Wallis,Lucinda L. Fulton,Robert S. Fulton,Vincent Magrini,Ryan Demeter,Todd Wylie,Cyriac Kandoth,Jeffrey R. Leonard,Abhijit Guha,Christopher A. Miller,Ding Li,Elaine R. Mardis
出处
期刊:Genome Research
[Cold Spring Harbor Laboratory]
日期:2012-12-05
卷期号:23 (3): 431-439
被引量:100
标识
DOI:10.1101/gr.142604.112
摘要
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.
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