Department of Medical Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Department of Medical Oncology, Jiangsu Province Hospital, Nanjing, China.
Pathol Oncol Res. 2021 Dec 14;27:1610075. doi: 10.3389/pore.2021.1610075. eCollection 2021.
Glutamine metabolism (GM) plays a critical role in hepatocellular carcinoma (HCC); however, a comprehensive methodology to quantify GM activity is still lacking. We developed a transcriptome-based GMScore to evaluate GM activity and investigated the association of GMScore with prognosis and therapeutic resistance. Two independent HCC cohorts with transcriptome data were selected from The Cancer Genome Atlas (TCGA, = 365) and the International Cancer Genome Consortium (ICGC, = 231). The expression of 41 GM-associated genes were used to construct and validate GMScore. Several genomic or transcriptomic biomarkers were also estimated. Tumor response to immune checkpoint inhibitors (ICIs) was predicted using the tumor immune dysfunction and exclusion algorithm. GMScore was closely correlated with patient characteristics, including stage, histology grade, alpha-fetoprotein level, and vascular invasion. High GMScore was an independent risk factor for overall survival (OS) in both cohorts (HR = 4.2 and 3.91, both < 0.001), superior to clinical indices and other biomarkers. High GMScore presented transcriptome features to indicate cell growth advantages and genetic stability, which was associated with poor OS of patients who received transcatheter arterial chemoembolization (TACE). High GMScore was also related to high expression of immune checkpoint genes, increased infiltration of regulatory T cells, and decreased infiltration of M1 macrophages. More importantly, high GMScore indicated poor predicted responses to ICIs, which could be verified in an ICI-treated melanoma cohort. In conclusion, GMScore is a strong prognostic index that may be integrated into existing clinical algorithms. A high GMScore may indicate resistance to TACE and ICIs based on its transcriptome and immune features. Validations using other HCC cohorts, especially ICI-treated HCC cohorts, are necessary.
谷氨酰胺代谢（GM）在肝细胞癌（HCC）中起着关键作用；然而，一种全面的量化 GM 活性的方法仍然缺乏。我们开发了一种基于转录组的 GMScore 来评估 GM 活性，并研究了 GMScore 与预后和治疗耐药性的相关性。从癌症基因组图谱（TCGA，n = 365）和国际癌症基因组联盟（ICGC，n = 231）中选择了两个具有转录组数据的独立 HCC 队列。使用 41 个 GM 相关基因的表达来构建和验证 GMScore。还估计了几种基因组或转录组生物标志物。使用肿瘤免疫功能障碍和排除算法预测肿瘤对免疫检查点抑制剂（ICIs）的反应。GMScore 与患者特征密切相关，包括分期、组织学分级、甲胎蛋白水平和血管侵犯。高 GMScore 是两个队列中总生存期（OS）的独立危险因素（HR = 4.2 和 3.91，均<0.001），优于临床指数和其他生物标志物。高 GMScore 表现出表明细胞生长优势和遗传稳定性的转录组特征，这与接受经导管动脉化疗栓塞（TACE）治疗的患者的不良 OS 相关。高 GMScore 还与免疫检查点基因的高表达、调节性 T 细胞的浸润增加和 M1 巨噬细胞的浸润减少有关。更重要的是，高 GMScore 表明对 ICIs 的反应较差，这可以在接受 ICI 治疗的黑色素瘤队列中得到验证。总之，GMScore 是一个强大的预后指标，可能会被整合到现有的临床算法中。根据其转录组和免疫特征，高 GMScore 可能表示对 TACE 和 ICIs 的耐药性。使用其他 HCC 队列进行验证，特别是接受 ICI 治疗的 HCC 队列，是必要的。
