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Clonal evolution of glioblastoma under therapy
Cited 480 time in
Web of Science
Cited 502 time in Scopus
- Authors
- Issue Date
- 2016-07
- Publisher
- Nature Publishing Group
- Citation
- Nature Genetics, Vol.48 No.7, pp.768-776
- Abstract
- Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-beta. Silencing LTBP4 in GBM cells leads to suppression of TGF-beta activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-b pathway as a potential therapeutic target in GBM.
- ISSN
- 1061-4036
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