Most glioblastoma patients have a dismal prognosis, although some survive several years. However, only few biomarkers are available to predict the disease course. EGR1 and EGR3 have been linked to glioblastoma stemness and tumour progression, and this study aimed to investigate their spatial expression and prognostic value in gliomas. Overall 207 gliomas including 190 glioblastomas were EGR1/EGR3 immunostained and quantified. A cohort of 21 glioblastomas with high P53 expression and available tissue from core and periphery was stained with double-immunofluorescence (P53-EGR1 and P53-EGR3) and quantified.EGR1 expression increased with WHO-grade, and declined by 18.9% in the tumour periphery vs. core (P = 0.01), while EGR3 expression increased by 13.8% in the periphery vs. core (P = 0.04). In patients with high EGR1 expression, 83% had methylated MGMT-promoters, while all patients with low EGR1 expression had un-methylated MGMT-promoters. High EGR3 expression in MGMT-methylated patients was associated with poor survival (HR = 1.98; 95%CI 1.22-3.22; P = 0.006), while EGR1 high/EGR3 high, was associated with poor survival vs. EGR1 high/EGR3 low (HR = 2.11; 95%CI 1.25-3.56; P = 0.005). EGR1 did not show prognostic value, but could be involved in MGMTmethylation. Importantly, EGR3 may be implicated in cell migration, while its expression levels seem to be prognostic in MGMT-methylated patients. Gliomas are the most common primary brain tumours, with the WHO grade IV glioblastoma multiforme (GBM) being the most malignant. In GBMs the current standard treatment with radical surgical resection, radiation and temozolomide therapy results in a median survival of approximately 15 months 1-3 , although some patients survive several years after diagnosis. Only few prognostic biomarkers are of use in daily practise, like the methylation status of O-6-Methylguanine-DNA Methyltransferase (MGMT) 4 and mutational status of the Isocitrate dehydrogenase 1/2 genes 5. Identification of additional novel biomarkers is therefore crucial in order to better stratify the patients. GBMs are characterized as highly vascularized, heterogeneous tumours with a profoundly infiltrative nature, leading to accelerated and aggressive disease progression. Nearly all GBMs recur after initial treatment efforts due to migrating tumour cells, which infiltrate the adjacent healthy brain parenchyma and escape surgical excision as well as radiation and temozolomide therapy. We have previously shown that these migrating tumour cells have a stem-cell like phenotype and are highly tumourigenic in vivo 6. Early growth response protein 1 (EGR1) and Early growth response protein 3 (EGR3) are C2H2-type zinc-finger proteins, which belong to the EGR-protein family of transcription factors. EGR1 has been proposed to regulate the expression of genes involved in cell proliferation, growth and cell differentiation 7,8. In addition, EGR3 has been implicated in immune regulation 9-11 and cell migration 12,13. Recently, EGR1 has been linked to the proliferation and self-rene...

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Introduction Gliomas are the most frequent primary brain tumors. For the most malignant glioma - the glioblastoma - the median survival is below 15 months. Since only few prognostic biomarkers are of benefit in daily practice, new markers are urgently needed. EGR1 and EGR3 are transcription factors involved in the regulation of cell-cycle and cell differentiation, but they have also been associated with migration of cancer cells. Studies have shown prognostic potential of EGR1 and EGR3 in breast-, gastric-, colorectal-, and prostate cancer. The purpose of this study was to investigate the expression and potential prognostic value of EGR1 and EGR3 in gliomas. Methods Samples of 214 gliomas were stained with anti-EGR1 and -EGR3 antibodies respectively. The stainings were assessed with a software-based digital classifier and a semi-quantitative scoring system. Kaplan-Meier estimates and Log-rank tests were used to compare survival distributions, and ROC-curve analysis with dichotomizing was applied to identify optimal cut-off values. Cox proportional hazards regression was performed to further investigate and identify independent prognostic variables. Results Both EGR1 and EGR3 were expressed in all glioma samples, but with considerable variation between tumors. EGR1 expression ranged from 1-83% positive cells and increased with WHO grade, while EGR3 expression ranged from 5-95% positive cells independent of WHO grade. High EGR1 levels were associated with improved survival in glioblastomas, while low EGR3 levels were associated with improved survival in WHO grade II and III gliomas. In glioblastomas, the EGR1 high/EGR3 low group was associated with improved patient survival when compared to the EGR1 low/EGR3 high group. Similar results were found in MGMT-promoter methylated glioblastomas, but not in MGMT-unmethylated glioblastomas. Cox proportional hazards regression showed that a high EGR1 fraction remained a significant prognostic variable when adjusted for confounders, both in all gliomas as one group (P=0.048) and glioblastomas exclusively (P=0.011). The combination of EGR1 high/EGR3 low in glioblastomas also remained significant after adjustment for confounders (P=0.030). Conclusion Both EGR1 and EGR3 proteins were expressed in all investigated gliomas. High levels of EGR1 seemed to be associated with improved patient survival in glioblastomas. In MGMT-promoter methylated glioblastomas, the EGR1 high/EGR3 low group was associated with improved patient survival when compared to the EGR1 low/EGR3 high group. Validation of the results in an additional patient cohort is needed, including analysis of prognostic value in different types of grade II and III gliomas. Citation Format: Arnon M. Knudsen, Ida Eilertsen, Susanne Kielland, Henning B. Boldt, Caspar S. Mellegaard, Sune Munthe, Bjarne W. Kristensen. Expression and prognostic value of EGR1 and EGR3 in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2649.

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