Łysiak Małgorzata, Smits Anja, Roodakker Kenney Roy, Sandberg Elisabeth, Dimberg Anna, Mudaisi Munila, Bratthäll Charlotte, Strandeus Michael, Milos Peter, Hallbeck Martin, Söderkvist Peter, Malmström Annika
Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden.
Department of Neuroscience and Physiology, Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
Cancers (Basel). 2021 Mar 31;13(7):1619. doi: 10.3390/cancers13071619.
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).
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.
LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, = 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, = 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.
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.
在包括胶质母细胞瘤（GBM）在内的癌症患病率中所观察到的性别差异的生物学原因仍知之甚少。其中一个被考虑的方面是性染色体的参与，尤其是Y染色体缺失（LOY）。
对105例异柠檬酸脱氢酶（IDH）野生型男性GBM患者的肿瘤进行液滴数字PCR检测，以检测Y染色体上10个基因的拷贝数变化。然后在来自TCGA的225例IDH野生型GBM中分析基因表达降低（基因缺失的替代指标），并使用Kaplan-Meier对数秩分析和最大选择秩统计量来确定两个队列中的总生存期截断值。
LOY与显著缩短的总生存期相关（7个月对14.6个月，P = 0.0016），在所研究的单个基因中，生存期与性别决定区Y基因（SRY）的缺失最显著相关（10.8个月对14.8个月，P = 0.0031）。基因集富集分析表明，表皮生长因子受体、血小板衍生生长因子受体和MYC原癌基因信号通路与低SRY表达相关。
我们的数据表明，Y染色体基因的缺失和基因表达降低，尤其是SRY，与男性GBM患者生存期缩短相关，并与胶质瘤发生的主要易感性通路有关。
