Tumor cell phenotype and heterogeneity differences in IDH1 mutant vs wild-type gliomas

Abstract

34Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition 35 and cellular interactions have not been well characterized. To gain new clinical-and biological-insights 36 into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated 37 multiplexed immunofluorescence single cell data for 43 protein markers across cancer hallmarks, in 38 addition to cell spatial metrics, genomic sequencing and magnetic resonance imaging (MRI) quantitative 39 features. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion differ between 40 IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted 41 in the MR imaging features of peritumoral edema and contrast enhancement volumes. Longer overall 42 survival for IDH1mt glioma patients may reflect generalized altered cellular, molecular, spatial 43 heterogeneity which manifest in discernable radiological manifestations. 44 45 48 While gliomas are relatively rare in the general population with an average annual age-adjusted 49 incidence of 6.2 per 100,000, these primary brain tumors contribute significant morbidity and mortality, 50 with glioblastoma carrying a 5-year survival rate of less than 6%(1). 51 52 The landscape of our knowledge about molecular features required for accurate diagnosis and prognosis 53 for glioma patients has advanced greatly in the last decade (2-5). Molecular subclassification highlights 54 different genetic underpinnings of glioblastoma (6), which offer some prognostic insight (7), likely 55 attributable, in part, to gene expression patterns influencing vulnerability to radiation (8). The World 56 Health Organization (WHO) classifies gliomas into defined categories based upon histologic and 57 molecular features and are assigned into four grades of increasing aggressiveness. Additionally, the 58 methylation status of O6-methylguanine-DNA methyltransferase (MGMT) has been implicated as a 59 useful biomarker for conferring tumor resistance to alkylating chemotherapies; methylation of the 60 MGMT promoter leads to transcriptional silencing of MGMT, which is associated with loss of MGMT 61 expression and increased response to alkylating chemotherapies such as temozolomide (TMZ) (9). 62 Analysis of DNA methylation from gliomas identified a DNA methylation-based phenotype, G-CIMP, 63 which is characterized by global hypermethylation of CpG islands and is predictive of increased survival; 64 this G-CIMP phenotype is associated with isocitrate dehydrogenase (IDH) mutation status (3, 4, 10). 4 65 66 IDH wild type (wt) in histologically defined low-grade gliomas is associated with poor clinical prognosis 67 that more resembles glioblastoma multiforme (GBM), which generally lack IDH mutation (IDHmt) (3, 11). 68 Conversely, IDH mutations are observed in the majority of lower-grade gliomas and are associated with 69 better clinical outcomes. In low-grade gliomas with IDH mutations, 1p/19q codeletion is further 70 associated wit...

NCOA4 is a Prognostic Biomarker Associated with Immune Infiltrates in Glioblastoma

“…Despite recent advances in comprehensive treatment strategies for GBM, GBM patients still have a poor prognosis [1]. Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized [2]. To date, only a few therapies are approved for the treatment of GBM with the main reasons being: 1) the apparent heterogeneity of the tumor leads to its speci c drug resistance 2) GBM can induce immunosuppression 3) the location of the intracranial tumor makes treatment more di cult 4) there is no clear biomarker for GBM to effectively diagnose and evaluate its prognosis [3].…”