Identification of Gender- and Subtype-Specific Gene Expression Associated with Patient Survival in Low-Grade and Anaplastic Glioma in Connection with Steroid Signaling

SIMPLE SUMMARY: Gliomas are primary brain tumors that are initially slow growing but progress to be more aggressive and, ultimately, fatal within a few years. They are more common in men than in women, suggesting a protective role for female hormones. By analyzing patient data collected in the public TGCA-LGG database, we have demonstrated a link between the expression level of key steroid biosynthesis enzymes or hormone receptors with patient survival, in ways that are dependent on gender and molecular subtype. We also determined the genes which expression associated with these actors of steroid signaling and the functions they perform, to decipher the mechanisms underlying gender-dependent differences. Together, these results establish, for the first time, the involvement of hormones in low-grade and anaplastic gliomas and provide clues for refining their classification and, thus, facilitating more personalized management of patients. ABSTRACT: Low-grade gliomas are rare primary brain tumors, which fatally evolve to anaplastic gliomas. The current treatment combines surgery, chemotherapy, and radiotherapy. If gender differences in the natural history of the disease were widely described, their underlying mechanisms remain to be determined for the identification of reliable markers of disease progression. We mined the transcriptomic and clinical data from the TCGA-LGG and CGGA databases to identify male-over-female differentially expressed genes and selected those associated with patient survival using univariate analysis, depending on molecular characteristics (IDH wild-type/mutated; 1p/19q codeleted/not) and grade. Then, the link between the expression levels (low or high) of the steroid biosynthesis enzyme or receptors of interest and survival was studied using the log-rank test. Finally, a functional analysis of gender-specific correlated genes was performed. HOX-related genes appeared to be differentially expressed between males and females in both grades, suggesting that a glioma could originate in perturbation of developmental signals. Moreover, aromatase, androgen, and estrogen receptor expressions were associated with patient survival and were mainly related to angiogenesis or immune response. Therefore, consideration of the tight control of steroid hormone production and signaling seems crucial for the understanding of glioma pathogenesis and emergence of future targeted therapies.