Pan-cancer analysis of the prognostic significance and oncogenic role of GXYLT2

Abstract

Growing evidence supports an oncogenic role for glucoside xylosyltransferase 2 (GXYLT2) in a number of malignancies. To evaluate the prognostic value and oncogenic function of GXYLT2 in diverse cancer types, we analyzed sequencing data from public databases on 33 tumor tissues and their corresponding normal tissues. We found that GXYLT2 was overexpressed in a number of tumors, and that its expression was positively correlated with disease progression and mortality in several major cancer types including stomach adenocarcinoma (STAD). GXYLT2 was also linked to tumor size, grade, and the immune and molecular subtypes of STAD. GO and KEGG pathway analyses of GXYLT2 co-expressed genes in STAD suggested that GXYLT2 possibly plays a role in epithelial-mesenchymal transition, extracellular matrix production and degradation, angiogenesis, apoptosis, as well as in tumor inflammation, such as cytokine production and T cell activation. Finally, prognostic nomograms were created and validated for predicting 1, 3, and 5-year survival of patients with STAD. Our findings indicate that GXYLT2 may play a role in tumorigenesis and tumor immunity, and it may serve as a prognostic marker and potential immunotherapeutic target for STAD and some other types of cancer.

Figure 1.

(A and B) GXYLT2 expression in 33 TCGA tumor types and corresponding normal control tissues. (A) GXYLT2 expression in tumor and normal tissues. All expression data were extracted from the TCGA database. *P < .05; **P < .01; ***P < .001, and ns indicates no significance. (B) GXYLT2 expression in tumors and normal tissues. Expression data for normal tissues were extracted from the TCGA and GTEx databases and merged. *P < .05; **P < .01; ***P < .001, and ns indicates no significance. (C) Genetic alterations of GXYLT2 in 33 TCGA tumor types analyzed through cBioPortal. GTEx = Genotype-Tissue Expression database, GXYLT2 = Glucoside Xylosyltransferase 2, TCGA = The Cancer Genome Atlas.

Figure 2.

Representative IHC images from the HPA database showing GXYLT2 protein expression in OV (A), STAD (B), and BRCA (C) tumor and normal tissues. Images on the left represent tumor tissues. Images in the middle and on the right represent normal tissues. BRCA = breast cancer, GXYLT2 = Glucoside Xylosyltransferase 2, HPA = Human Protein Atlas, IHC = immunohistochemistry, OV = ovarian cancer, STAD = stomach adenocarcinoma.

Figure 3.

Correlation between GXYLT2 expression and OS. (A) Kaplan–Meier curves showing the correlation between GXYLT2 expression and OS in BLCA, GBM, KICH, STAD, and KIRC. (B) Forest plots showing the relationship between GXYLT2 expression and OS in the 33 TCGA tumor types. BLCA = bladder urothelial carcinoma, GBM = glioblastoma multiforme, GXYLT2 = Glucoside Xylosyltransferase 2, KICH = kidney chromophobe, KIRC = kidney renal clear cell carcinoma, OS = overall survival, STAD = stomach adenocarcinoma, TCGA = The Cancer Genome Atlas.

Figure 4.

Correlation between GXYLT2 expression and tumor stage in ACC (A), BLCA (B), COAD (C), ESCA (D), HNSC (E), KIRC (F), LUAD (G), STAD (H), and TGCT (I). BLCA = bladder urothelial carcinoma, COAD = colon adenocarcinoma, GXYLT2 = Glucoside Xylosyltransferase 2, HNSC = head and neck squamous cell carcinoma, KIRC = kidney renal clear cell carcinoma, LUAD = lung adenocarcinoma, STAD = stomach adenocarcinoma, TGCT = testicular germ cell tumors.

Figure 5.

Radar plots showing association of GXYLT2 expression with TMB (A) and MSI (B) in 33 TCGA tumor types. Lines and numbers in each plot represent correlation coefficients and ranges, respectively. *P < .05, **P < .01, and ***P < .001. GXYLT2 = Glucoside Xylosyltransferase 2, MSI = microsatellite instability, TCGA = The Cancer Genome Atlas, TMB = tumor mutational burden.

Figure 6.

GXYLT2 associations with stromal, immune, and ESTIMATE scores across 33 TCGA cancers. ***P < .001. GXYLT2 = Glucoside Xylosyltransferase 2, TCGA = The Cancer Genome Atlas.

Figure 7.

GXYLT2 expression in human STAD. (A) GXYLT2 mRNA expression in human STAD and normal tissues based on TCGA data. (B) GXYLT2 mRNA expression in human STAD and normal tissues based on combined GTEx and TCGA data. (C) Representative IHC images showing GXYLT2 protein expression in normal (upper panel) and STAD (lower panel) human tissue. IHC experiments were conducted in house. *P < .05, **P < .01, and ***P < .001. GTEx = Genotype-Tissue Expression database, GXYLT2 = Glucoside Xylosyltransferase 2, IHC = immunohistochemistry, STAD = stomach adenocarcinoma, TCGA = The Cancer Genome Atlas.

Figure 8.

GXYLT2 association with demographic and clinicopathological characteristics of STAD patients based on TCGA data. (A) GXYLT2 association with age, gender, grade, primary tumor size, and metastasis. (B) Heatmaps of age, gender, grade, stage, tumor size, lymph node metastasis (N), and distant metastasis (M) of patients with low and high GXYLT2 expression. (C) Kaplan–Meier survival curves of patients with low and high GXYLT2 expression. Left, OS; Right, PFS. *P < .05 and **P < .01. GXYLT2 = Glucoside Xylosyltransferase 2, OS = overall survival, PFS = progression-free survival, TCGA = The Cancer Genome Atlas.

Figure 9.

Prognostic nomograms for predicting the OS of STAD patients. (A) Univariate (left) and multivariate (right) Cox regression analyses of OS in a training cohort of patients. (B) Prognostic nomograms created from training data for predicting the 1-, 3-, and 5-yr OS (left) and plots showing their performance with regard to their predictive accuracy in a validation cohort of patients (right). For predicting OS using a nomogram, the value for each predictor is determined by drawing a line upward to the reference point line, adding the points, and drawing a line downward from the total points line to find the predicted probability of node positivity. OS = overall survival, STAD = stomach adenocarcinoma.

Figure 10.

GXYLT2 expression was associated with STAD molecular (A) and immune (B) subtypes. GXYLT2 = Glucoside Xylosyltransferase 2, STAD = stomach adenocarcinoma.

Figure 11.

GXYLT2 co-expression analysis for functional classification in STAD. (A) Genes co-expressed with GXYLT2 as identified from STAD expression data extracted from TCGA. (B and C) GO and KEGG enrichment analysis of genes co-expressed with GXYLT2 in STAD. GO = Gene Ontology, GXYLT2 = Glucoside Xylosyltransferase 2, KEGG = Kyoto Encyclopedia of Genes and Genomes, TCGA = The Cancer Genome Atlas.