The impact of heme biosynthesis regulation on glioma aggressiveness: Correlations with diagnostic molecular markers

Abstract

BackgroundThe prognosis of diffusely infiltrating glioma patients is dismal but varies greatly between individuals. While characterization of gliomas primarily relied on histopathological features, molecular markers increasingly gained importance and play a key role in the recently published 5th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its paramount importance in oxygen transport, energy production and drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grade and survival. The aim of the current study was to correlate this heme biosynthesis mRNA expression signature with diagnostic molecular markers and investigate its continued prognostic relevance.Materials and methodsIn this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, chromosome 7 + /10- aneuploidy, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q codeletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature for correlation with distinct molecular glioma markers/molecular subgroups and performed survival analyses.ResultsA total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype (p < 0.0005), without 1p19q codeletion (p < 0.0005), with homozygous CDKN2A/B loss (p < 0.0005) and with EGFR amplification (p = 0.001). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with molecular subgroup aggressiveness (p < 0.0005), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas. Finally, the heme biosynthesis mRNA expression signature was a statistically significant survival predictor after multivariate correction for all molecular markers (p < 0.0005).ConclusionOur data demonstrate a significant correlation between heme biosynthesis regulation and diagnostic molecular markers and a prognostic relevance independent of these established markers. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.

Mapping high-grade glioma immune infiltration to 5-ALA fluorescence levels: TCGA data computation, classical histology, and digital image analysis

“…For instance, intratumoral regions such as the necrotic core or the peripheral part of the infiltration zone show weak or no visible 5-ALA fluorescence even though they harbour tumor cells [ 4 ]. Or, for example, areas with strong 5-ALA fluorescence represent compact tumor regions with high cellularity, mitotic activity, microvessel density and presumably high aggressiveness [ 5 – 7 ]. However, at present, several fundamental facts of 5-ALA biology are not established.…”

Clusterin Is a Prognostic Biomarker of Lower-Grade Gliomas and Is Associated with Immune Cell Infiltration

“…Even with standard treatment, the recurrence and progression of tumor are still ineluctable for patients [21]. Increasing attention has been paid to prognosisassociated molecular markers in gliomas, such as 1p19q co-deletion, IDH mutations, and p53 mutation, as their application in clinical practice for gliomas has been demonstrated [22]. In addition, promising novel therapies, such as gene therapy and immunotherapy, are constantly being established [23,24].…”

Attributing Meaning to Molecular Interaction Networks by Leveraging Clinical and Omic Data: The Missing Link between Tumor Biology and Treatment Strategies in Glioma

“…by Li et al, STRING can be employed to connect prognosis-related genes to the glioma microenvironment, which in their study was accomplished by employing TCGA and GSE4290 data sets to arrive at several previously lesser known or unknown genes that share both a link to the glioma microenvironment and prognosis [7]. Mischkulnig et al employed TCGA data and STRING to link heme biosynthesis regulation to glioma aggressiveness by connecting heme biosynthesis RNA expression to molecular markers associated with glioma grade [8]. The KEGG (Kyoto Encyclopedia of Genes and Genomes) database [3], initially created in 1995, is a conglomerate of 16 databases and functions by gathering published literature to map omic signals to pathways (Figure 2).…”