Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data
Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data
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DOI：
10.1126/scitranslmed.aao5253
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发表时间：
2019-01-02
影响因子：
17.1
通讯作者：
Rubin, Joshua B.
中科院分区：
文献类型：
--
作者：
Yang, Wei;Warrington, Nicole M.;Rubin, Joshua B.
人类疾病发病率和结果的性别差异已得到广泛承认，但在大多数情况下，对这种差异的了解还不够，无法采取针对性别的治疗方法。胶质母细胞瘤（GBM），最常见的恶性脑肿瘤，提供了一个很好的例子。尽管在发病率方面存在明确的差异，并且出现了结局差异的迹象，但在分子水平上区分男性和女性GBM或允许特异性靶向这些生物学差异的见解很少。在这里，使用定量成像为基础的措施的反应，我们发现，标准治疗是更有效的女性相比，男性患者GBM。然后，我们应用计算算法将GBM转录组和结果数据相关联，并确定GBM的性别特异性分子亚型，其中细胞周期和整合素信号传导分别是男性和女性患者生存的关键决定因素。通过一组男性和女性患者来源的GBM细胞系中基因表达与体外化疗敏感性之间的相关性，进一步确定了细胞周期和整合素信号通路特征的临床相关性。总之，这些结果表明，更精确的GBM分子亚型可以实现通过性别特异性分析，并改善所有患者的结果可能是通过定制治疗的性别差异的分子机制。
Sex differences in the incidence and outcome of human disease are broadly recognized but, in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that standard therapy is more effective in female compared with male patients with GBM. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical relevance of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together, these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms.