Glutamine Metabolism Scoring Predicts Prognosis and Therapeutic Resistance in Hepatocellular Carcinoma

Abstract

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, n = 365) and the International Cancer Genome Consortium (ICGC, n = 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 p < 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.

A novel glutamine metabolism-related gene signature for prognostic prediction in patients with lung adenocarcinoma

“…Recently, Ying et al [12] suggested a multigene model related to GM could predict prognosis and therapeutic resistance in hepatocellular carcinoma. A risk model based on GMScore exhibited superior than other biomarkers for prognostic prediction.…”

“…Glutamine metabolism-related genes (names as GMRGs) were extracted from the Gene Ontology (GO) initiative and published literatures [11,12]. The 3 level of RNA-seq data and clinical characteristics of LUAD were obtained from TCGA website (https://portal.gdc.cancer.gov/).…”

Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy

“…High GS expression appears to be associated with poor prognosis in HCC, but this conclusion is controversial. [17][18][19][20] It has been reported that GS positive (GS+) HCC tumors have a higher differentiation grade [17] and that patients with GS+ HCC tumors experience better overall survival (OS) after radiofrequency thermal ablation. [18] In contrast, reports from other groups have shown that GS may enhance metastasis and recurrence in HCC, [19] and patients with higher GS expression have worse OS when receiving postoperative adjuvant transcatheter arterial chemoembolization.…”

“…Immunostaining of both GS and Arg1 is widely used in clinical pathology to discriminate HCC from intrahepatic cholangiocarcinoma, though the role of GS and Arg1 immunostaining in the molecular classification of HCC is still undefined. High GS expression appears to be associated with poor prognosis in HCC, but this conclusion is controversial [17–20] . It has been reported that GS positive (GS+) HCC tumors have a higher differentiation grade [17] and that patients with GS+ HCC tumors experience better overall survival (OS) after radiofrequency thermal ablation [18] .…”

“…It has been reported that GS positive (GS+) HCC tumors have a higher differentiation grade [17] and that patients with GS+ HCC tumors experience better overall survival (OS) after radiofrequency thermal ablation [18] . In contrast, reports from other groups have shown that GS may enhance metastasis and recurrence in HCC, [19] and patients with higher GS expression have worse OS when receiving postoperative adjuvant transcatheter arterial chemoembolization [20] . Overall, the association between GS expression and sensitivity to systemic chemotherapy, such as sorafenib adjuvant therapy, remains unclear.…”