Role of RIPK1 in Diffuse Gliomas pathology

Abstract

ABSTRACTPurposeThe aim of the present work was to investigate the role of Receptor-interacting protein kinase 1 (RIPK1) both in mutated and wild type isocitrate dehydrogenase (IDH) Diffuse Gliomas (DG).Patients and MethodsWe analyzed RIPK1 mRNA expression in DG databases from The Cancer Genome Atlas (TCGA) containing clinical, genomic and transcriptomic information from 661 patients. Transcriptomic studies (mRNA expression levels, correlation heatmaps, survival plots and Gene Ontology and meta-analysis of immune gene signatures) were performed with USC Xena and R. Statistical significance was set at p-values less than 0.05.ResultsThe results showed a lower survival probability in patients belonging to the high RIPK1 expression subgroup compared to those samples with low RIPK1 expression. We also observed a higher expression of RIPK1 in wtIDH samples compared to those with mIDH. In order to further characterize the role of RIPK1 in DG, we performed a Gene Ontology and Pathway Enrichment Analysis using the Xena platform’s differential expression tool. The results showed that RIPK1 is involved in inflammatory and immune responses. Hence, the expression levels of some of the genes involved in the following molecular processes crucial for cancer progression were studied: proliferation, epithelial-mesenchymal transition, immune cell infiltration and cell death pathways. Briefly, the results showed significant differences in genes related to increased cellular dedifferentiation, proinflammatory cell death pathways and tumor infiltrating immune cells gene signatures (Welch’s t-test).ConclusionRIPK1 over-expression is associated with a poor prognosis in DG. This fact, together with our results suggest that RIPK1 may play a crucial role in glioma pathogenesis highlighting the need to take into account RIPK1 expression levels for decision making when choosing or designing therapeutic alternatives.CONTEXT SUMMARYKey ObjectiveEvaluate the role of the Receptor-interacting protein kinase 1 (RIPK1) in Diffuse Gliomas (DG) pathology through an exhaustivein silicopatient database analysis.Knowledge generatedWe demonstrated that RIPK1 is overexpressed in more aggressive DG and correlates with clinical attributes associated with poor prognosis. In addition, our analyses showed that high RIPK1 expression correlates with key genes involved in pro inflammatory cell death pathways and an increased expression of immune gene signatures suggesting greater immunological infiltration in the tumor.RelevanceOur results from patient database analyses propose RIPK1 as a new relevant molecular prognosis marker for DG. Our findings are in concordance with different preclinical studies and provide additional information that can be useful for decision making when choosing therapeutic strategies and for the development of novel therapeutic approaches such as gene or immunotherapy.This work was presented inXIII Argentine Congress of Bioinformatics and Computational Biology (XIII CAB2C), XIII International Conference of the Iberoamerican Society of Bioinformatics (XIII SoIBio) and III Annual Meeting of the Ibero-American Artificial Intelligence Network for Big BioData (III RiaBio).