Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients

Abstract

Background: Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY). Methods: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan–Meier log-rank analysis and maximally selected rank statistics for cut-off determination. Results: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression. Conclusion: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.

Crosstalk between SOX Genes and Long Non-Coding RNAs in Glioblastoma

“…However, no significant sex-related differences in transcriptomes of gliomas have been observed [ 28 ], but it seems that the existing differences in survival are attributed to the role of the male sex chromosome in patients’ samples. It has been shown that deletion of the SRY gene, loss of genes located on the Y chromosome, and complete loss of the Y chromosome in GBM samples negatively influence the survival of male patients [ 29 ]. SRY/chromosome Y status might partially explain the mechanisms underlying the observed sex disparities regarding incidence, prognosis, drug toxicity, clinical outcome, and therapeutic response in GBM [ 30 ].…”