In silico analysis of genetic, transcription, epigenetic and protein changes of EGFR-PI3K-AKT-mTOR signaling pathway participants in diffuse gliomas of the brain

Abstract

Difuzni gliomi heterogena su skupina tumora s agresivnim biološkim ponašanjem. Unatoč novim molekularnim saznanjima razlike između patohistoloških tipova su nedovoljno istražene. U ovoj in silico analizi istraživali smo uloge 8 gena, sudionika signalizacije EGFR-PI3K-AKT-mTOR, u gliomima mozga. Analiza AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN i PIK3AP1 napravljena je korištenjem podataka javno dostupne baze cBioPortal za tumorsku genomiku i transkriptomiku. Genske, transkripcijske, epigenetičke te proteinske promjene obrađene su na 751 uzorku (62 difuzna astrocitoma, 129 anaplastičnih astrocitoma te 560 glioblastoma). Rezultati su pokazali promjene u broju kopija (CNA od engl. copy number alteration) gena PTEN (76%), PIK3AP1 i CHUK (75% svaki), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) te GSK3β (18%). Učestalost promjena razlikovala se između gradusa. Najveći broj CNA imali su glioblastomi u kojima su EGFR, PIK3AP1 i PTEN bili promijenjeni u 89%, CHUK u 88%, a AKT2 u 43% analiziranih uzoraka. Kruskal-Wallis test pokazao je značajnu razliku u metilaciji i ekspresiji mRNA ispitivanih gena između pojedinih gradusa. Korelacija rezultata sugerira da se geni AKT1, AKT2, EGFR i PIK3AP1 ponašaju kao onkogeni, a geni AKT3, CHUK, GSK3β i PTEN poput tumor supresora. Rezultati doprinose saznanjima o molekularnim razlikama između patohistoloških tipova glioma te mogu poslužiti za bolju klasifikaciju i poboljšanje metoda liječenja.Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior. Despite new molecular findings, the differences between pathohistological types need to be explained better. In this in silico analysis, we investigated participants of EGFR-PI3K-AKT-mTOR signaling in brain gliomas. The analysis of AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 was performed using data from the publicly available cbBioPortal database. 751 samples (62 diffuse astrocytoma, 129 anaplastic astrocytoma and 560 glioblastomas) revealed changes at genetic, transcriptome, epigenome, and protein levels. The results showed copy number alterations (CNA) of PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%). The highest number of CNA had glioblastomas with alterations in EGFR, PIK3AP1, and PTEN in 89%, CHUK in 88%, and AKT2 in 43%. The Kruskal-Wallis test showed a significant difference in the methylation and expression of the mRNA of the tested genes between individual grades. The correlation of the results suggests that AKT1, AKT2, EGFR, and PIK3AP1 behave like oncogenes, while AKT3, CHUK, GSK3β, and PTEN act like tumor suppressors. The results contribute to the knowledge of molecular differences between pathohistological types of gliomas and may serve for better classification and treatment methods improvement