GABRQ expression is a potential prognostic marker for patients with clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Novel biomarkers of ccRCC may provide crucial information on tumor features and prognosis. The present study aimed to determine whether the expression of γ-aminobutyric acid (GABA) A receptor subunit θ (GABRQ) could serve as a novel prognostic marker of ccRCC. GABA is the main inhibitory neurotransmitter in the brain that activates the receptor GABA_A, which is comprised of three subunit isoforms: GABRA3, GABRB3 and GABRQ. A recent study reported that GABRQ is involved in the initiation and progression of hepatocellular carcinoma; however, the role of GABRQ in ccRCC remains unknown. In the present study, clinical and transcriptomic data were obtained from cohorts of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Differential GABRQ expression levels among early (TI and II), late (TIII and IV), nonmetastatic (M0) and metastatic (M1, primary tumor) stages of ccRCC samples were then identified. Furthermore, the use of GABRQ as a prognostic gene was analyzed using Uno's C-index based on the time-dependent area under the curve (AUC), the AUC of the receiver operating characteristic curve at 5 years, the Kaplan-Meier survival curve and multivariate analysis. The survival curve analysis revealed that low GABRQ mRNA expression was significantly associated with a poor prognosis of ccRCC (P<0.001 and P=0.0012 for TCGA and ICGC data, respectively). In addition, analyses of the C-index and AUC values further supported this discriminatory power. Furthermore, the prognostic value of GABRQ mRNA expression was confirmed by multivariate Cox regression analysis. Taken together, these results suggested that GABRQ mRNA expression may be considered as a novel prognostic biomarker of ccRCC.

Keywords: International Cancer Genome Consortium; The Cancer Genome Atlas; clear cell renal cell carcinoma; prognosis; γ-aminobutyric acid receptor A subunit θ.

Figure 1.

Flowchart of the present study. AUC, area under the curve; ICGA, International Cancer Genome Consortium; TCGA, The Cancer Genome Atlas.

Figure 2.

Comparison of GABRQ mRNA expression among early (TI and II), late (TIII and IV), nonmetastatic (M0), and metastatic (M1, primary tumor) stages of ccRCC samples from TCGA and ICGC cohorts. (A-C) GABRQ expression values in ccRCC samples from TCGA cohort. (D-F) GABRQ expression values in ccRCC samples from ICGC cohort. ccRCC, clear cell renal cell carcinoma; GABRQ, γ-aminobutyric acid receptor A subunit θ; ICGA, International Cancer Genome Consortium; TCGA, The Cancer Genome Atlas.

Figure 3.

GABRQ gene expression in tumors. The copy number of GABRQ in tumors in the Oncomine database corresponds to the GSE20306 dataset (n=449) (36). The x-axis represents the number of patients with different types of cancer: 0, Normal (n=4); 1, Bladder (n=9); 2, Brain and central nervous system (n=17); 3, Breast (n=21); 4, Cervical (n=7); 5, Colorectal (n=21); 6, Esophageal (n=4); 7, Gastric (n=5); 8, Head and neck (n=6); 9, Kidney (n=8); 10, Leukemia (n=33); 11, Liver (n=9); 12, Lung (n=78); 13, Lymphoma (n=41); 14, Melanoma (n=12); 15, Myeloma (n=5); 16, Other (n=7); 18, Pancreatic (n=9); 19, Prostate (n=5) and 20, Sarcoma (n=20). GABRQ, γ-aminobutyric acid receptor A subunit θ.

Figure 4.

Kaplan-Meier estimation of GABRQ mRNA expression as a prognostic biomarker in patients with ccRCC. The association of GABRQ gene expression with overall survival among patients from TCGA was examined. Gene expression was analyzed for (A) all patients, (B) stage I and II, (C) stage III and IV, (D) T stage I and II, (E) T stage III and IV, (F) M stage 0, and (G) M stage 1. P-values were calculated by the log-rank test and are provided in the bottom left of each plot. ccRCC, clear cell renal cell carcinoma; GABRQ, γ-aminobutyric acid receptor A subunit θ; TCGA, The Cancer Genome Atlas; M0, non-metastatic; M1, primary tumor.

Figure 5.

Kaplan-Meier estimation of GABRQ mRNA expression as a prognostic biomarker in patients with ccRCC. The association of GABRQ gene expression with overall survival among patients from the ICGC was examined. Gene expression was analyzed for (A) all patients, (B) stage I and II, (C) stage III and IV, (D) T stage I and II, (E) T stage III and IV, (F) M stage 0, and (G) M stage 1. P-values were calculated by the log-rank test and are provided in the bottom left of each plot. ccRCC, clear cell renal cell carcinoma; GABRQ, γ-aminobutyric acid receptor A subunit θ; ICGC, International Cancer Genome Consortium; M0, non-metastatic; M1, primary tumor.

Figure 6.

Time-dependent AUC and ROC curve analysis at 5 years according to GABRQ mRNA expression in TCGA and ICGC samples. Analysis of GABRQ gene expression in TCGA (red) and ICGC (blue) samples according to (A) time-dependent AUC and (B) ROC curve at 5 years. C-index values are provided in the bottom right corner of each plot. AUC, area under the curve; GABRQ, γ-aminobutyric acid receptor A subunit θ; ICGA, International Cancer Genome Consortium; ROC, receiver operating characteristic; TCGA, The Cancer Genome Atlas.