The sex‐dependent role of the androgen receptor in glioblastoma: results of molecular analyses

Abstract

We sought to analyse the androgen receptor (AR) in glioblastoma (GBM) due to the location of the AR gene on chromosome X, often reported with shorter survival and higher prevalence of GBM among males. Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 91 fresh-frozen GBM samples and 170 formalin-fixed, paraffinembedded samples collected at Link€ oping University Hospital. The freshfrozen cohort was also subjected to pyrosequencing methylation analysis of 17 CpG sites in the AR promoter. Additionally, the gene expression of AR was analysed in the fresh-frozen cohort and The Cancer Genome Atlas (TCGA) cohort of isocitrate dehydrogenase wild-type primary GBM (135 females and 219 males). The association of AR expression and overall survival (OS) was tested with Kaplan-Meier log rank analysis after dichotomisation by maximally selected rank statistics. We found that AR CN alterations were more common in female GBM. AR gene expression correlated with methylation levels of different CpG sites in males and females but there was no difference in expression between sexes. Survival analysis of TCGA cohort revealed the opposite effect of AR overexpression on OS of males and females, with high AR expression correlating with shorter OS in females and longer OS in males. Additional gene set enrichment analysis showed that AR expression correlated with DNA repair response, especially in the male group. In summary, we found that high AR gene expression in GBM exhibits sex-dependent effects on patient survival, which, for males, is linked to DNA repair response.

Contribution of the Testosterone Androgen Receptor–PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

“…Thus, upregulation of the AR gene expression in the microenvironment of human GBM may be due to augmentation of testosterone. In GBM, upregulation of the AR gene can alter DNA repair responses, immunity, and the hormone status in the tumor microenvironment [ 10 , 11 ]. In contrast, levels of AR mRNA in pan-TCGA cancer types, including BLCA, CESC, CHOL, HNSC, KICH, LIHC, LUAD, LUSC, READ, THCA, THYM, and UCEC, were downregulated compared to their respective normal tissues.…”

“…Fascinatingly, targeting AR signaling is widely investigated for treatment of multiple types of cancers, especially in prostate cancer [ 9 ]. Łysiak et al showed the positive correlation of AR gene expression with the DNA repair response in the microenvironment of GBM tissues [ 10 ]. Our present results obtained from a bioinformatics search show that there were 5 AR binding elements found in the 5′ promoter region of the PARD3B gene.…”

“…Interestingly, targeting AR signaling has been widely investigated and potentially applied to treat multiple types of cancers, especially prostate cancer [ 9 ]. Recently, Łysiak et al reported the positive correlation of AR gene expression with the DNA repair response in the microenvironment of GBM tissues [ 10 ]. Expression of the AR gene is also positively related to the survival of cancer patients, especially male cases.…”