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Sex differences in expression of immune elements emerge in children, young adults and mice with osteosarcoma
Biology of Sex Differences ( IF 7.9 ) Pub Date : 2021-01-06 , DOI: 10.1186/s13293-020-00347-y
Lauren J Mills 1, 2 , Logan G Spector 1, 2, 3 , David A Largaespada 1, 2, 4, 5, 6 , Lindsay A Williams 1, 2, 3, 4
Affiliation  

Males < 40 years old are more likely to be diagnosed with and die from osteosarcoma (OS). The underlying mechanisms may depend on sex differences in immune response. We used SEER data to estimate survival differences between males and females aged < 40 years at OS diagnosis. In NCI TARGET-OS cases, we determined sex differences in gene expression, conducted Gene Set Enrichment Analysis (GSEA), and applied the LM22 signature to identify biologic sex differences. We compared sex differences in gene expression profiles in TARGET-OS to those observed in Sleeping Beauty (SB) transposon mutagenesis accelerated Trp53R270H-mutant mouse-OS and healthy adult osteoblasts. Males had worse 17-year overall survival than females (SEER p < 0.0001). From 87 TARGET-OS cases, we observed 1018 genes and 69 pathways that differed significantly by sex (adjusted p < 0.05). Pathway and gene lists overlapped with those from mice (p = 0.03) and healthy osteoblasts (p = 0.017), respectively. Pathways that differed significantly by sex were largely immune-based and included the PD-1/PD-L1 immunotherapy pathway. We observed sex differences in M2 macrophages (LM22; p = 0.056) and M1-M2 macrophage transition (GSEA; p = 0.037) in TARGET-OS. LM22 trends were similar in mice. Twenty-four genes differentially expressed by sex in TARGET-OS had existing cancer therapies. Sex differences in OS gene expression were similar across species and centered on immune pathways. Identified sex-specific therapeutic targets may improve outcomes in young individuals with OS.

中文翻译:

患有骨肉瘤的儿童、年轻人和小鼠中出现免疫元件表达的性别差异

< 40 岁的男性更有可能被诊断出骨肉瘤 (OS) 并死于骨肉瘤 (OS)。潜在的机制可能取决于免疫反应的性别差异。我们使用 SEER 数据来估计 OS 诊断时年龄 < 40 岁的男性和女性之间的生存差异。在 NCI TARGET-OS 案例中,我们确定了基因表达的性别差异,进行了基因集富集分析 (GSEA),并应用 LM22 签名来识别生物性别差异。我们将 TARGET-OS 中基因表达谱的性别差异与睡美人 (SB) 转座子诱变加速的 Trp53R270H 突变小鼠 OS 和健康成年成骨细胞中观察到的基因表达谱的性别差异进行了比较。男性的 17 年总生存率低于女性 (SEER p < 0.0001)。从 87 个 TARGET-OS 病例中,我们观察到 1018 个基因和 69 个通路因性别而存在显着差异(调整后 p < 0.05)。通路和基因列表分别与小鼠 (p = 0.03) 和健康成骨细胞 (p = 0.017) 的通路和基因列表重叠。性别差异显着的途径主要是基于免疫的,包括 PD-1/PD-L1 免疫治疗途径。我们在 TARGET-OS 中观察到 M2 巨噬细胞 (LM22;p = 0.056) 和 M1-M2 巨噬细胞转变 (GSEA;p = 0.037) 的性别差异。小鼠中的 LM22 趋势相似。TARGET-OS 中按性别差异表达的 24 个基因已有癌症疗法。OS 基因表达的性别差异在不同物种之间是相似的,并且集中在免疫途径上。确定的性别特异性治疗靶点可能会改善年轻 OS 患者的预后。
更新日期:2021-01-07
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