Abstract 1556: Long non-coding RNA <i>WNT5A-AS1</i> shows sex-dimorphic differences in survival for males with glioblastoma

Abstract

<p>Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival time of 12-15 months and 5-year survival rate of 5%. Despite the application of advanced genetics and biological breakthroughs in GBM, the outcome for GBM remains dismal. Previous genome-wide association studies (GWAS) for GBM shows that the incidence rate for GBM in males is 1.6 times higher in men than women, with men displaying overall worse outcomes. In-vivo studies in gender-matched isogenic murine astrocytic cell lines show that the rate of astrocytic transformation is higher in males than in females, corroborating the GWAS findings in human GBM. Thus, understanding how sex effects GBM biology may provide insight into the mechanism of gliomagenesis and response to therapy. To explore the molecular mechanisms by which transformation of GBM increases in males, we used DESeq2 to assess differentially expressed genes between male and female patients. We found that a long non-coding RNA WNT5A-AS1 is overexpressed in males [log2(fold change) of 1.40; FDR = 0.036], regardless of cofounding factors such as IDH1 status, age, and race. Next, we examined if expression of WNT5A-AS1 is correlated with survival within male patients versus female patients in the TCGA-GBM dataset. In males, WNT5A-AS1’s expression is significantly correlated with patient overall survival (P = 0.042, N=109), but not in female (P = 0.585, N=60). Male patients with high expression of WNT5A-AS1 display poor survival outcomes compared to males with low expression. WNT5A-AS1 is located in the upstream, promoter region of WNT5A. Q-PCR quantification of WNT5A expression increases in male GBM specimens as compared to GBM specimens from females. The role that WNT5A-AS1 plays in regulating WNT5A expression is unclear to date. Interestingly, WNT5A expression shows a positive correlation with patient survival in males, with high expression displaying better survival outcomes (p=0.0272). We have data obtained from a subset of patient samples showing an inverse relationship between WNT5A and WNT5A-AS1 expression. This suggests that there may be an inverse correlation between WNT5A-AS1 and WNT5A expression, which elucidates that WNT5A-AS1 may be regulating WNT5A expression. Current ongoing studies will evaluate the role of WNT5A-AS1/WNT5A in sex-differences of GBM progression.</p>