Clonal evolution of glioblastoma under therapy.

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-?. Silencing LTBP4 in GBM cells leads to suppression of TGF-? activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-? pathway as a potential therapeutic target in GBM.

SUBMITTER: Wang J 

PROVIDER: S-EPMC5627776 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature