成人弥漫性神经胶质瘤（ADG）的性别差异在临床上已得到充分证实，但其潜在的分子机制仍不清楚。在这里，我们的目标是揭示 ADG 中每种性别独特的分子特征和细胞组成，以理解性别在疾病病因学中的作用。我们使用多个独立的神经胶质瘤患者数据集量化了 ADG 转录组的性别差异。接下来，我们深入研究单细胞景观，以检查基因表达和细胞组成的性别差异。为了探索性别如何影响疾病进展，我们分析了原发性和复发性 ADG 病例的配对样本，旨在识别分子和细胞特征中性别特异性的差异。我们的分析表明，异柠檬酸脱氢酶 (IDH) 基因和肿瘤微环境的突变表现为性别差异分子富集的主要影响因素。在IDHwt肿瘤中，发现神经元信号通路中的基因在男性肿瘤中富集，而缺氧和炎症反应通路中的基因在女性肿瘤中富集。这种模式在 IDHmut 神经胶质瘤中发生了逆转。我们假设这些差异可能归因于性别之间的异质细胞组成。使用单细胞数据，我们分别观察了 IDHwt 和 IDHmut 肿瘤中细胞状态、细胞组成和细胞间相互作用的性别差异的独特模式。此外，通过比较配对的原发性和复发性 ADG 样本中的分子变化，我们确定了复发性肿瘤的分子特征和细胞组成方面的性别特异性差异。我们的结果提供了 ADG 性别差异的全面多层次表征，这些发现提供了新颖的见解每种性别的神经胶质瘤疾病进展。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Sex differences in adult diffuse glioma (ADG) are well-established clinically, yet the underlying molecular mechanisms remain inadequately understood. Here, we aim to reveal molecular features and cellular compositions unique to each sex in ADG to comprehend the role of sex in disease etiology.We quantified sex differences in transcriptome of ADG using multiple independent glioma patient datasets. Next, we delved into the single-cell landscape to examine sex differences in gene expression and cellular composition. To explore how sex influences disease progression, we analyzed paired samples from primary and recurrent ADG cases, aiming to identify sex-specific differences in molecular and cellular features.Our analysis revealed that mutations in isocitrate dehydrogenase (IDH) genes and the tumor microenvironment emerged as primary influencers of sex-differential molecular enrichments. In IDHwt tumors, genes in neuronal signaling pathway are found to be enriched in male tumors, while genes in hypoxia and inflammatory response pathways are enriched in female tumors. This pattern was reversed in IDHmut gliomas. We hypothesized that these distinctions could be attributed to heterogeneous cellular composition between sexes. Using single-cell data, we observed distinctive patterns of sex differences in cell states, cell composition and cell-cell interaction in IDHwt and IDHmut tumors separately. Further, by comparing molecular changes in paired primary and recurrent ADG samples, we identified sex-specific differences in molecular characteristics and cellular compositions of recurrent tumors.Our results provide a comprehensive multi-level characterization of sex differences in ADG, such findings provide novel insights into glioma disease progression in each sex.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.