Significance of Amphiregulin (AREG) for the Outcome of Low and High Grade Astrocytoma Patients

Background: Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor which levels was shown to have a tight coherence with various types of cancer. AREG was also designated to be a promising marker for several types of cancer however precious little data about AREG role in the most frequent and generally lethal human brain tumours - astrocytomas reported up to date. The aim of the study was to investigate how AREG changes at epigenetic and expression levels reflect on astrocytoma malignancy and patient outcome. Methods: In total 205 low and high grade astrocytoma samples (15 pilocytic astrocytomas, 56 diffuse astrocytomas, 32 anaplastic astrocytomas and 102 glioblastomas) were used for target mRNA, protein expression and DNA methylation analysis applying qRT-PCR, Western-Blot and MS-PCR assays, respectively. Results: Present research revealed that AREG expression level and methylation in cancer tissue is dependent on the grade of astrocytoma. GBM tissue disclosed elevated AREG mRNA expression but reduced AREG protein level as compared to grade II and grade III astrocytomas (p<0.001). Increased methylation frequency was also more abundant in GBM (74%) than grade I, II and III astrocytomas (25%, 34%, and 36%, respectively). The survival analysis revealed relevant differences in patient overall survival between AREG methylation, mRNA and protein expression groups. Kaplan-Meier analysis encompassing only malignant tumours showed similar results indicating that AREG is associated with astrocytoma patient survival independently from astrocytoma grade. Conclusions: Current findings demonstrate that AREG appearance is associated with patient survival as well as astrocytomas malignancy indicating its influence on tumour progression and suggest its applicability as a promising marker.