P11.43 Deletions on Y chromosome are associated with shorter survival in glioblastoma

Abstract

Abstract BACKGROUND Apart from few exceptions, men are more likely to be diagnosed with cancer during their lifetime, including glioblastoma (GBM), but the gender-related differences in GBM are poorly understood. Loss of chromosome Y (LOY) in peripheral blood cells is associated with physiological ageing, but also with disorders like cardiovascular disease, Alzheimer’s disease and different cancer types. In this study, we determined deletions on Y chromosome in tumor tissue of male patients with GBM, and studied the impact of LOY on survival. MATERIAL AND METHODS Ten genes, serving as markers, were selected on both arms of chromosome Y for copy number analysis with droplet digital PCR (ddPCR), enabling detection of loss of a marker in a fraction of the tumor cells used for DNA extraction. A total of 114 tumor samples from male patients were used, derived from a cohort of IDH wild type GBM patients treated with standard radio-chemo therapy. For 61 of these 114 patients, corresponding blood samples were available and analyzed. Different cut-off values were tested for each marker and Kaplan-Meier log-rank analysis was used to estimate overall survival. The mRNA expression for nine of the ten tested genes was available in TCGA, and 225 IDH wild type male GBM were included in a separate survival analysis, where median value of expression was used as group separator. RESULTS Fractional loss, as well as gain of markers was detected. Decreased copy number of the following markers was associated with significantly shorter survival; amelogenin Y-linked (AMELY) (13.5 vs. 19.3 months, p=0.017), neuroligin 4 Y-linked (NLGN4Y) (11.8 vs. 18.9 months, p=0.03) and sex determining region Y (SRY) (10.3 vs. 18.7 months, p=0.002). Additional analysis of SRY in the blood samples verified that copy number alterations were predominantly present in tumors. Survival analysis using mRNA expression data from TCGA showed that reduced expression of SRY was associated with significantly shorter OS (13.8 vs. 19.8 months, p=0.008), but no significant correlation with OS for any of the other markers. CONCLUSION Our data suggests a clonal or at least sporadic occurrence of fractional loss of Y chromosome markers in GBM, as detected with ddPCR. Interestingly, such dosage changes may contribute to shorter survival in men and explain some of the sex disparity seen in GBM. More research is needed to elucidate the molecular mechanisms of LOY and the role of specific Y-linked genes in GBM but also other diseases.