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

TY - JOUR

T1 - Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature

AU - Wojtas, Bartosz

AU - Gielniewski, Bartlomiej

AU - Wojnicki, Kamil

AU - Maleszewska, Marta

AU - Mondal, Shamba S

AU - Nauman, Pawel

AU - Grajkowska, Wieslawa

AU - Glass, Rainer

AU - Schüller, Ulrich

AU - Herold-Mende, Christel

AU - Kaminska, Bozena

PY - 2019/2/27

Y1 - 2019/2/27

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.3390/cancers11030284

DO - 10.3390/cancers11030284

M3 - SCORING: Journal article

C2 - 30818875

VL - 11

JO - CANCERS

JF - CANCERS

SN - 2072-6694

IS - 3

ER -