Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature

Abstract

Gliosarcoma is a very rare brain tumor reported to be a variant of glioblastoma (GBM), IDH-wildtype. While differences in molecular and histological features between gliosarcoma and GBM were reported, detailed information on the genetic background of this tumor is lacking. We intend to fill in this knowledge gap by the complex analysis of somatic mutations, indels, copy number variations, translocations and gene expression patterns in gliosarcomas. Using next generation sequencing, we determined somatic mutations, copy number variations (CNVs) and translocations in 10 gliosarcomas. Six tumors have been further subjected to RNA sequencing analysis and gene expression patterns have been compared to those of GBMs. We demonstrate that gliosarcoma bears somatic alterations in gene coding for PI3K/Akt (PTEN, PI3K) and RAS/MAPK (NF1, BRAF) signaling pathways that are crucial for tumor growth. Interestingly, the frequency of PTEN alterations in gliosarcomas was much higher than in GBMs. Aberrations of PTEN were the most frequent and occurred in 70% of samples. We identified genes differentially expressed in gliosarcoma compared to GBM (including collagen signature) and confirmed a difference in the protein level by immunohistochemistry. We found several novel translocations (including translocations in the RABGEF1 gene) creating potentially unfavorable combinations. Collected results on genetic alterations and transcriptomic profiles offer new insights into gliosarcoma pathobiology, highlight differences in gliosarcoma and GBM genetic backgrounds and point out to distinct molecular cues for targeted treatment.

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

“…The PI3K pathway is often activated by the silence or genetic loss of phosphatase and tensin homolog and/or the overexpression of protein kinase B [22,23]. The PI3K pathway plays a vital role in carcinogenesis, drug resistance, and programmed cell death of melanoma cells [24][25][26][27][28][29]. Therefore, this pathway is a promising target for melanoma therapy.…”

Optic pathway gliosarcoma: A very rare location for a rare disease

“…GS is generally wild-type - lacks mutations in the genes IDH1/2 [ 3 , 5 , 6 , 7 ]. They have some genetic alterations similar to glioblastomas, such as Phosphatase and tensin homolog (PTEN and PIK3) mutations [7] .…”

“…GS is generally wild-type - lacks mutations in the genes IDH1/2 [ 3 , 5 , 6 , 7 ]. They have some genetic alterations similar to glioblastomas, such as Phosphatase and tensin homolog (PTEN and PIK3) mutations [7] . However, collagen gene signature ( COL1A1, COL1A2, COL3A1, COL6A@ , and COL6A3 ) are the gliosarcomas' main biomarkers, differentiating them from glioblastomas [7] .…”

KIF3C Promotes Proliferation, Migration, and Invasion of Glioma Cells by Activating the PI3K/AKT Pathway and Inducing EMT

“…It has been reported that the PI3K/AKT pathway regulates tumor cell survival, growth, motility, angiogenesis, and metabolism in a variety of cancers, including GBM [ 25 , 26 ]. Inhibition of the PI3K/AKT pathway may result in GBM cell death and slow tumor progression [ 27 , 28 ]. It is reported that KIF3C was related to the PI3K/AKT pathway, which lacked a confirmatory experiment [ 29 ].…”