Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases

Abstract

OBJECTIVE: Glioblastoma, the most common and lethal brain tumor, is also one of the most defying forms of malignancies in terms of treatment. Integrated genomic analysis has searched deeper into the molecular architecture of GBM, revealing a new sub-classification and promising precision in the care for patients with specific alterations. METHOD: Here, we present the classification of a Brazilian glioblastoma cohort into its main molecular subtypes. Using a high-throughput DNA sequencing procedure, we have classified this cohort into proneural, classical and mesenchymal sub-types. Next, we tested the possible use of the overexpression of the EGFR and CHI3L1 genes, detected through immunohistochemistry, for the identification of the classical and mesenchymal subtypes, respectively. RESULTS: Our results demonstrate that genetic identification of the glioblastoma subtypes is not possible using single targeted mutations alone, particularly in the case of the Mesenchymal subtype. We also show that it is not possible to single out the mesenchymal cases through CHI3L1 expression. CONCLUSION: Our data indicate that the Mesenchymal subtype, the most malignant of the glioblastomas, needs further and more thorough research to be ensure adequate identification.

Plasmatic membrane toll-like receptor expressions in human astrocytomas

“…Mesenchymal GBM subtype presented higher TLR4 and TLR6 mRNA median levels than other molecular subtypes in our cohort ( S1 Fig .) [ 36 ]. However, given the reduced sample number, particularly for the proneural and mesenchymal GBM cases in this cohort, statistical significance was not achieved.…”

“…Our previous analysis of PTEN status in our GBM cohort demonstrated 24.32% and 26.66% of PTEN deletion, and 59.45% and 66.66% of PTEN phosphorylation in classical and mesenchymal subtypes, respectively ( S5 Fig .) [ 36 , 55 ], demonstrating more prevalent PTEN loss of function in the classical subtype. These PTEN alterations may lead to a decreased inhibition over TIRAP ( Fig 6 ) and consequent TLR canonical pathway activation.…”

Receptor do tipo Toll 4 dentre os TLRs de membrana plasmática possui um papel na malignidade de astrocitomas

“…Loss of function of PTEN may occur by its deletion or phosphorylation (65,96). Our previous analysis of PTEN status in our GBM cohort demonstrated 24.32% and 26.66% of PTEN deletion, and 59.45% and 66.66% of PTEN phosphorylation in classical and mesenchymal subtypes, respectively ( Figure 14) (77,96), demonstrating more prevalent PTEN loss of function in the classical subtype. These PTEN alterations may lead to a decreased inhibition over TIRAP ( Figure 15) and consequent TLR canonical pathway activation.…”

“…The analysis of TLRs expression levels for GBM molecular subtypes showed that mesenchymal GBM subtype presented higher TLR4 and TLR6 mRNA median levels than other molecular subtypes in our cohort ( Figure 3) (77). However, given the reduced sample number, particularly for the proneural and mesenchymal GBM cases in this cohort, statistical significance was not achieved.…”

O papel de STMN1 e MELK em astrocitoma humano

“…Os coeficientes de correlações dos níveis de expressão foram positivos e significativas para todas as análises em pares: MELK e STMN1 Correlação entre os níveis de expressão de MELK, STMN1 e FOXM1 em casos de GBM da casuística do TCGA. Houve correlações positivas dos níveis de expressões de MELK e STMN1 (A), FOXM1 e STMN1 (B), e também MELK e FOXM1 (C) (teste Spearman-rho).Os níveis de expressão de MELK, STMN1 e FOXM1 foram também analisados nos casos de GBM da casuística do laboratório de acordo com os subtipos moleculares(Galatro et al, 2017). Os resultados estão apresentados na Figura 7.…”