Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations

Abstract

Background: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the developing central and peripheral nervous systems during embryogenesis. Human telomerase reverse transcriptase (h-TERT) protein resumption is the main process of preservation of telomeres that maintains DNA integrity. The present study aims to evaluate the prognostic role of ALK-1 and h-TERT protein expression and their correlation with ALK gene alterations in glioblastoma multiforme (GBM). Methods: The current study is a retrospective study on a cohort of patients with GBM (n = 53) that attempted to detect ALK gene alterations using fluorescence in situ hybridization. ALK-1 and h-TERT proteins were evaluated using immunohistochemistry. Results: Score 3 ALK-1 expression was significantly associated with male sex, tumor multiplicity, Ki labeling index (Ki LI), and type of therapeutic modality. Score 3 h-TERT expression exhibited a significant association with Ki LI. ALK gene amplifications (ALK-A) were significantly associated with increased Ki LI and therapeutic modalities. Score 3 ALK-1 protein expression, score 3 h-TERT protein expression, and ALK-A were associated with poor overall survival (OS) and progression-free survival (PFS). Multivariate analysis for OS revealed that ALK gene alterations were an independent prognostic factor for OS and PFS. Conclusions: High protein expression of both ALK-1 and h-TERT, as well as ALK-A had a poor impact on the prognosis of GBM. Further studies are needed to establish the underlying mechanisms.

Evaluation of Immunohistochemical Expression of ALK-1 in Gliomas, WHO Grade 4 and Its Correlation with IDH1-R132H Mutation Status

“…This difference might be ascribed to variations in environmental factors and sample size. As for the correlation of ALK-1 immunoexpression with the gender of the studied cases, we reported higher expression in males (14/16); a finding consistent with Karagkounis et al 2017 [ 17 ], Elsers et al (021 [ 18 ], and Hakeem et al 2021 [ 19 ]. The established male predominance in GBs might clarify those concordant findings.…”

“…In the present study, ALK-1 expression was higher in cases older than the mean age compared to those younger than the mean age, disagreeing with Ferguson et al 2016 [ 20 ], yet, consistent with Karagkounis et al 2017 [ 17 ], Elsers et al 2021 [ 18 ], Hakeem et al 2021 [ 19 ] as they all noted more frequent ALK overexpression in older cases. This difference might be ascribed to variations in environmental factors and sample size.…”

“…This finding was in harmony with Kulig et al 2012 [ 16 ] where ALK-1 was expressed in 17.9% of their GB cases. However, Chiba et al 2017 [ 14 ], Karagkounis et al 2017 [ 17 ], Elsers et al 2021 [ 18 ] showed much higher positivity rates; 84.9%, 49.2% & 70.6% respectively. Conversely, Hakeem et al 2021 [ 19 ] showed ALK-1 positivity in only 3 of their 60 studied astrocytoma cases, 2 of which were grade 4.…”

Mapping chromatin remodelling in glioblastoma identifies epigenetic regulation of key molecular pathways and novel druggable targets

“…To identify pathways directly regulated by HM in GIC, we selected the concordant genes (activating HM/upregulation of expression and repressive HM/downregulation of expression) for each HM and performed GSEA (Fig.S5e and b, table S2). In the first instance we confirmed the results of the SHM analysis that pathways known to play a role in glioblastoma pathogenesis are epigenetically regulated, including pathways related to neoplastic transformation (Receptor Tyrosin Kinase (RTK) signalling (EBRR2) 28 , WNT signalling 29 GPCR signalling 30 ), neuronal systems (potassium channels 31 ), cellular response to stress and ALK signalling 32 33 , as well as genes involved in circadian clock regulation 34 35 36 (Fig.S5e and table S2). Pathways involved in modulation of the inflammatory microenvironment via interferon signalling (antigen presentation, cytokine signalling and interferon signalling) 37 were also identified, in keeping with an intrinsic regulation of the inflammasome mediated by the redistribution of HM in tumour cells (Fig.S5e and table S2).…”

“…Interestingly, we also identified pathways regulated by a combination of histone modifications, gain of H3K4me3, H3K36me3 and H3K27ac or loss of H3K27me3 respectively, including cellular response to stress and ALK signalling, for which a dysregulation has been described in glioblastoma 32 33 . Pathways involved in the modulation of the inflammatory microenvironment via interferon signalling (antigen presentation, cytokine signalling and interferon signalling) which were shown to regulate cell death and mesenchymal phenotype 37 are epigenetically regulated in GIC, hence demonstrating a cell intrinsic regulation of the inflammasome mediated by the redistribution of HM in tumour cells.…”