Huang Yingbo, Shan Yuting, Zhang Weijie, Printzis Christina, Pesce Lorenzo, Stover Danielle, Stanhope Catherine, Stranger Barbara E, Huang Rong Stephanie
Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota, USA.
Neuro Oncol. 2025 Feb 10;27(2):430-444. doi: 10.1093/neuonc/noae207.
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 the 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 the 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 multilevel characterization of sex differences in ADG; such findings provide novel insights into glioma disease progression in each sex.
成人弥漫性胶质瘤（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未得到充分理解。在此，我们旨在揭示ADG中每种性别的独特分子特征和细胞组成，以理解性别在疾病病因中的作用。
我们使用多个独立的胶质瘤患者数据集对ADG转录组中的性别差异进行了量化。接下来，我们深入研究单细胞图谱，以检查基因表达和细胞组成方面的性别差异。为了探究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方面的性别特异性差异。
我们的分析表明，异柠檬酸脱氢酶（IDH）基因突变和肿瘤微环境是性别差异分子富集的主要影响因素。在IDH野生型肿瘤中，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。在IDH突变型胶质瘤中，这种模式则相反。我们推测这些差异可能归因于两性之间细胞组成的异质性。利用单细胞数据，我们分别在IDH野生型和IDH突变型肿瘤中观察到细胞状态、细胞组成和细胞间相互作用方面独特的性别差异模式。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在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特征；这些发现为每种性别的胶质瘤疾病进展提供了新的见解。
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