Clonal Evolution of Glioblastoma under Therapy

Glioblastoma (GBM) constitutes the most common and aggressive primary brain tumor. To better understand how GBM evolves we analyzed longitudinal genomic and transcriptomic data of 114 patients. The analysis reveals a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern together with estimates of evolutionary rates suggest that the relapse associated clone typically preexisted years before diagnosis. 15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature. We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-ß. Silencing LTBP4 in GBM cells leads to TGF-ß activity suppression and decreased proliferation. In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-ß pathway as a potential therapeutic target in GBM.