Elevated Serum IL-6 as a Negative Prognostic Biomarker in Glioblastoma: Integrating Bioinformatics and Clinical Validation
Sup Kim, Kyung Hwan Kim, Hee‐Won Jung, Eun-Oh Jeong, Han-Joo Lee, Jeanny Kwon, Hyon‐Jo Kwon, Seung-Won Choi, Hyeon‐Song Koh, Seon‐Hwan Kim
Abstract
Background: Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, necessitating the discovery of reliable serum prognostic biomarkers.This study aimed to investigate the prognostic value of serum Interleukin-6 (IL-6) in GBM patients.Methods: Bioinformatics analysis via gene set enrichment analysis was conducted on The Cancer Genome Atlas RNA-seq data to explore the pathways enriched in samples with high IL-6 expression.The Tumor IMmune Estimation Resource database was used to analyze the association between IL-6 expression and immune cell infiltration.To validate the role of IL-6 in a clinical setting, a retrospective cohort study was conducted on newly diagnosed GBM patients.Serum IL-6 levels were repeatedly measured at key milestone time points, and their correlation with survival data was analyzed.Results: Bioinformatics analysis revealed that high IL-6 expression is associated with the activation of procancer pathways, that there is a positive correlation between IL-6 expression and immune cell infiltration in GBM.Between March 2021 and September 2023, 36 GBM patients and their serum IL-6 measurements at various time points were included in the clinical data analyses.Elevated serum IL-6 levels at baseline, with a cutoff of 7pg/mL, were identified in 11 patients (30.6%).In the multivariate analyses for overall survival (OS), elevated IL-6 was a significant risk factor (p = 0.048), along with unfavorable surgical resection (p = 0.039) and O6-methylguanine-DNA methyltransferase promotor unmethylation (p = 0.027).The median actuarial OS of the high initial IL-6 group was significantly shorter than that of the low initial IL-6 group (6.4 vs. 19.7 months, p < 0.001).However, IL-6 levels at other time points were not related to patient prognosis.Conclusion: Elevated IL-6 mRNA expression is correlated with the activation of procancer pathways, increased immune cell infiltration, and poor prognosis in GBM patients.In addition, elevated serum IL-6 at baseline is a negative prognostic factor confirmed in a clinical study.Serum IL-6 may be a potential prognostic biomarker enhancing the management of GBM.