Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3β, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3β alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3β–mutated and wild-type tumors. GSK-3β was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3β–mutated tumors were observed for B cells (P = 0.018), monocytes (P = 0.002), dendritic cells (P = 0.005), neutrophils (P = 0.0003), and endothelial cells (P = 0.014). GSK-3β mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3β–mutated tumors compared with wild type in colorectal cancer (P = 0.03), endometrial cancer (P = 0.05), melanoma (P = 0.02), ovarian carcinoma (P = 0.0001), and uterine sarcoma (P = 0.002). Overall, GSK-3β molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3β mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3β mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.

中文翻译：

---

糖原合酶激酶 3 β (GSK-3b) 基因组改变在癌症中的景观

糖原合酶激酶-3β (GSK-3β) 是一种丝氨酸/苏氨酸激酶，与许多癌症的发病机制有关，涉及细胞周期调节、细胞凋亡和免疫反应。小分子 GSK-3β 抑制剂目前正在进行临床研究。肿瘤测序揭示了 GSK-3β 的基因组改变，但缺乏对恶性肿瘤基因组景观的评估。本研究评估了来自两个数据库的 >100,000 个肿瘤以分析 GSK-3β 的改变。分析了各种癌症类型的 GSK-3β 表达和免疫细胞浸润数据，并比较了 GSK-3β 突变型和野生型肿瘤之间的程序性死亡配体 1 (PD-L1) 表达。GSK-3β 的突变率为 1%。大多数突变残基位于激酶结构域中，GSK-3β 底物结合口袋中经常发生突变。子宫内膜样癌是最常见的突变 (4%) 肿瘤，在鳞状组织中最常观察到拷贝数变异。对于 GSK-3β 突变的肿瘤，在 B 细胞（P = 0.018）、单核细胞（P = 0.002）、树突状细胞（P = 0.005）、中性粒细胞（P = 0.0003）和内皮细胞（P = 0.014）。GSK-3β mRNA 表达在黑色素瘤中最高。GSK-3β突变肿瘤中PD-L1表达频率高于结直肠癌（P = 0.03）、子宫内膜癌（P = 0.05）、黑色素瘤（P = 0.02）、卵巢癌（P = 0.0001）的野生型）和子宫肉瘤（P = 0.002）。总体而言，在大约 1% 的实体瘤中检测到 GSK-3β 分子改变，具有 GSK-3β 突变的肿瘤显示出 B 细胞浸润增加的微环境，和 GSK-3β 突变与所选组织学中 PD-L1 表达增加有关。这些结果促进了对 GSK-3β 复合信号网络与致癌作用和免疫反应相关关键通路接口的理解。