A Comprehensive Prognostic Analysis of Tumor-Related Blood Group Antigens in Pan-Cancers Suggests That SEMA7A as a Novel Biomarker in Kidney Renal Clear Cell Carcinoma

Abstract

Blood group antigen is a class of heritable antigenic substances present on the erythrocyte membrane. However, the role of blood group antigens in cancer prognosis is still largely unclear. In this study, we investigated the expression of 33 blood group antigen genes and their association with the prognosis of 30 types of cancers in 31,870 tumor tissue samples. Our results revealed that blood group antigens are abnormally expressed in a variety of cancers. The high expression of these antigen genes was mainly related to the activation of the epithelial-mesenchymal transition (EMT) pathway. High expression of seven antigen genes, i.e., FUT7, AQP1, P1, C4A, AQP3, KEL and DARC, were significantly associated with good OS (Overall Survival) in six types of cancers, while ten genes, i.e., AQP1, P1, C4A, AQP3, BSG, CD44, CD151, LU, FUT2, and SEMA7A, were associated with poor OS in three types of cancers. Kidney renal clear cell carcinoma (KIRC) is associated with the largest number (14 genes) of prognostic antigen genes, i.e., CD44, CD151, SEMA7A, FUT7, CR1, AQP1, GYPA, FUT3, FUT6, FUT1, SLC14A1, ERMAP, C4A, and B3GALT3. High expression of SEMA7A gene was significantly correlated with a poor prognosis of KIRC in this analysis but has not been reported previously. SEMA7A might be a putative biomarker for poor prognosis in KIRC. In conclusion, our analysis indicates that blood group antigens may play functional important roles in tumorigenesis, progression, and especially prognosis. These results provide data to support prognostic marker development and future clinical management.

Keywords: blood group antigen; cancer biomarker; pan-cancers; prognosis; tumor-associated antigens (TAAs).

Figure 1

The flow diagram of this study. (A) The schematic diagram shows how the analysis route of the prognostic value of blood group antigen genes in pan-cancers was calculated. (B) The chart shows that 33 blood group antigen genes in 29 blood group systems were analyzed in this study. (C) The frequency of published records of blood group antigens as cancer prognostic markers.

Figure 2

The differential expression of the blood group antigen system gene mRNA expression in pan-cancers. The threshold was set using following parameters: |log2(fold change)| ≥ 1 and p value < 0.05. The number in the cell represents the number of datasets that meets the thresholds. The color intensity (red or blue) is directly proportional to the significance level of upregulation or downregulation, respectively.

Figure 3

The relationship between the expression of blood group antigen system genes and prognostic clinical features in different types of cancers in TCGA dataset. Significant correlation is shown in color (p < 0.05). (A) Association between gene expression and overall survival across human cancers. Unsupervised hierarchical clustering and heatmap for the 33 blood group antigens across 30 cancers based on LOGpc results. Red represents unfavorable outcome (blue represents favorable), i.e., the gene is associated with shorter (or longer) survival. NS: Not Significant. (B–E) High AQP1 expression was related to good OS in LUCA and KIRP, to poor OS in LGG and UVM. (F) The number of cancer types with prognosis potency. (G) The number of each blood group gene in the prognosis of different cancer types. (H) Association between gene expression and cancer stage across human cancers. Earlier/Advance: the gene is associated with earlier/advance stage (Spearman correlation test: p < 0.05). NS: Not Significant. (I) Association between gene expression and tumor grade across human cancers. Lower/Higher: the gene is associated with lower/higher grade (Spearman correlation test: p < 0.05). NS: Not Significant. Cancer types: ACC (adrenocortical carcinoma), BLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (cholangiocarcinoma), COAD (colon adenocarcinoma), ESCA (esophageal carcinoma), GBM (glioblastoma multiforme), HNSC (head and neck squamous cell carcinoma), KICH (kidney chromophobe), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), MESO (mesothelioma), OV (ovarian serous cystadenocarcinoma), PAAD (pancreatic adenocarcinoma), PCPG (pheochromocytoma and paraganglioma), PRAD (prostate adenocarcinoma), READ (rectum adenocarcinoma), SARC (sarcoma), SKCM (skin cutaneous melanoma), STAD (stomach adenocarcinoma), TGCT (testicular germ cell tumors), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma), UCS (uterine carcinosarcoma), and UVM (uveal melanoma).

Figure 4

SEMA7A is highly expressed in KIRC cases and is associated with patients’ bad prognosis. (A) SEMA7A protein levels in normal and primary tumors. Log2 Spectral count ratio values from CPTAC were first normalized within each sample profile, then normalized across samples (****, p < 0.0001). (B–E) Kaplan–Meier curves of overall survival (OS), progression free interval (PFI), disease specific survival (DSS) and progression free survival (PFS) for KIRC patients with low and high SEMA7A mRNA expression. SEMA7A mRNA expression is associated with poor overall survival in the TCGA dataset of 523 KIRC patients (p < 0.05).

Figure 5

Functional and pathway enrichment analyses of DEGs between low and high SEMA7A KIRC subgroups (cut-off: 50%). (A) GO enrichment analysis in cellular components (CC), molecular functions (MF) and biological processes (BP). (B) KEGG enrichment analysis of DEGs.