Clonal evolution of glioblastoma under therapy

Abstract

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

Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors

“…However, in three patients point mutations detected in primary tumors were lost upon recurrence while novel EGFR mutations turned up in recurrent glioblastomas of six patients. These findings would be in line with a branched tumor evolution model, suggesting that recurrent glioblastomas following therapy may develop from minor subclones of the respective primary tumor (64,65). In addition, it is possible that EGFR point mutations detected exclusively in recurrent tumors are induced by therapy, in particular in case of C-G to T-A transitions that are known to be related to DNA-alkylating treatment with temozolomide (66).…”

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

“…Likewise, the generality of EV properties across larger panels of GBM and GSC isolates or subtypes, and their representation in intact tissues are still to be addressed more fully, and are currently under study. Moreover, therapy-induced evolution of GSCs [55] is likely to impact EV profiles, as we recently documented [56], while intra-tumoural interactions of different GSC population may also involve EV-dependent signals [28]. …”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…Subgroupspecific therapeutic designs will need to be implemented based on the final biological phenotype, which integrates all sources of tumor heterogeneity. For example, drugs that inhibit epigenetic modifiers could reprogram the genomes of gliomas with mutant IDH1/2 enzymes (25), while the use of temozolomide in such tumors may need to be reconsidered, as it induces a hypermutated phenotype (27)(28)(29).…”

“…Segregating clones based on the presence of independent or shared mutations has revealed part of the tumor development process (27)(28)(29)(35)(36)(37). The clonal evolution model posits that tumor formation is initiated in a cell of origin and is followed by the accumulation of single or multiple somatic genetic alterations, leading to advantages in survival or growth (38).…”