期刊
NATURE NEUROSCIENCE
卷 20, 期 10, 页码 1329-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nn.4620
关键词
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资金
- Yale SBI/Genetics Startup Fund
- Damon Runyon [DRG-2117-12, DFS-13-15]
- Melanoma Research Alliance [412806, 16-003524]
- St. Baldrick's Foundation [426685]
- American Cancer Society [IRG 58-012-54]
- Breast Cancer Alliance
- Cancer Research Institute (CLIP)
- AACR [499395]
- DoD [W81XWH-17-1-0235]
- NIH/NCI [1U54CA209992, 5P50CA196530-A10805, 4P50CA121974-A08306]
- NCCRMSE
- ETH Zurich
- McGovern Institute
- NSF [1122374]
- NIH [R01-CA133404, R01-GM034277, T32GM007499]
- NIH (CCNE)
- Skoltech Center
- Casimir-Lambert Fund
- NIH/NIMH [5DP1-MH100706, 1R01-MH110049]
- NSF
- NY Stem Cell Foundation
- HHMI
- Poitras Foundation
- Simons Foundation
- Paul G. Allen Family Foundation
- Vallee Foundation
- NIH MSTP training grant [T32GM007205]
- RJ Anderson Fellowship
- CRI Irvington Postdoctoral Fellowship
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.
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