Identification of cancer/testis antigens related to gastric cancer prognosis based on co-expression network and integrated transcriptome analyses


Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Gastric cancer is a worldwide life-threatening cancer. The underlying cause of it is still unknown. We have noticed that some cancer/testis antigens (CTAs) are up-regulated in gastric cancer. The role of these genes in gastric cancer development is not fully understood. The main aim of the current study was to comprehensively investigate CTAs' expression and function in stomach adenocarcinoma (STAD).
Materials and Methods: A comprehensive list of CTA genes was compiled from different databases. Transcriptome profiles of STAD were downloaded from the cancer genome atlas (TCGA) database and analyzed. Differentially-expressed CTAs were identified. Pathway enrichment analysis, weighted gene correlation network analysis (WGCNA), and overall survival (OS) analysis were performed on differentially-expressed CTA genes.
Results: Pathway enrichment analysis indicates that CTA genes are involved in protein binding, ribonucleic acid processing, and reproductive tissues. WGCNA showed that six differentially-expressed CTA genes, namely Melanoma antigen gene (MAGE) family member A3, A6, A12 and chondrosarcoma associated gene (CSAG) 1, 2, and 3, were correlated. Up-regulation of MAGEA11, MAGEC3, Per ARNT SIM domain containing 1 (PASD1), placenta-specific protein 1 (PLAC1) and sperm protein associated with the nucleus X-linked family member (SPANXB1) were significantly associated with lower OS of patients.
Conclusion: MAGEA11, MAGEC3, PASD1, PLAC1, and SPANXB1 can be investigated as prognostic biomarkers in basic and clinical studies. Further functional experiments are needed to understand the exact interaction mechanisms of these genes.


Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.  Back to cited text no. 1
Etemadi A, Safiri S, Sepanlou SG, Ikuta K, Bisignano C, Shakeri R, et al. The global, regional, and national burden of stomach cancer in 195 countries, 1990–2017: A systematic analysis for the Global Burden of Disease study 2017. Lancet Gastroenterol Hepatol 2020;5:42-54.  Back to cited text no. 2
Hamashima C, Systematic Review Group and Guideline Development Group for Gastric Cancer Screening Guidelines. Update version of the Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol 2018;48:673-83.  Back to cited text no. 3
Aida K, Yoshikawa H, Mochizuki C, Mori A, Muto S, Fukuda T, et al. Clinicopathological features of gastric cancer detected by endoscopy as part of annual health checkup. J Gastroenterol Hepatol 2008;23:632-7.  Back to cited text no. 4
Canakis A, Pani E, Saumoy M, Shah SC. Decision model analyses of upper endoscopy for gastric cancer screening and preneoplasia surveillance: A systematic review. Therap Adv Gastroenterol 2020;13:1-22.  Back to cited text no. 5
Mokadem I, Dijksterhuis WP, van Putten M, Heuthorst L, de Vos-Geelen JM, Haj Mohammad N, et al. Recurrence after preoperative chemotherapy and surgery for gastric adenocarcinoma: A multicenter study. Gastric Cancer 2019;22:1263-73.  Back to cited text no. 6
Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol 2018;24:2818-32.  Back to cited text no. 7
Lee T, Teng TZ, Shelat VG. Carbohydrate antigen 19-9-tumor marker: Past, present, and future. World J Gastrointest Surg 2020;12:468-90.  Back to cited text no. 8
Chen M, Zhao H. Next-generation sequencing in liquid biopsy: Cancer screening and early detection. Hum Genomics 2019;13:34.  Back to cited text no. 9
Gibbs ZA, Whitehurst AW. Emerging contributions of cancer/testis antigens to neoplastic behaviors. Trends Cancer 2018;4:701-12.  Back to cited text no. 10
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCGAbiolinks: An R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 2016;44:e71.  Back to cited text no. 11
Bethesda (MD): National Library of Medicine (US) NC for BI. GENE; 2004. [cited 2021 04 15] Available from:  Back to cited text no. 12
Belinky F, Nativ N, Stelzer G, Zimmerman S, Iny Stein T, Safran M, et al. PathCards: Multi-source consolidation of human biological pathways. Database (Oxford) 2015;2015:bav006.  Back to cited text no. 13
“HUGO Gene Nomenclature Committee at the European Bioinformatics Institute.” HUGO Gene Nomenclature Committee; 2020. [cited 2021 04 10] Available from:  Back to cited text no. 14
Almeida LG, Sakabe NJ, de Oliveira AR, Silva MC, Mundstein AS, Cohen T, et al. CTdatabase: A knowledge-base of high-throughput and curated data on cancer-testis antigens. Nucleic Acids Res 2009;37:D816-9.  Back to cited text no. 15
Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559.  Back to cited text no. 16
Law CW, Chen Y, Shi W, Smyth GK. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 2014;15:R29.  Back to cited text no. 17
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498-504.  Back to cited text no. 18
Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g: Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res 2019;47:W191-8.  Back to cited text no. 19
Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: Integrating viruses and cellular organisms. Nucleic Acids Res 2021;49:D545-51.  Back to cited text no. 20
Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS One 2010;5:e13984.  Back to cited text no. 21
Kucera M, Isserlin R, Arkhangorodsky A, Bader GD. AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations. F1000Res 2016;5:1717.  Back to cited text no. 22
Mendoza-Figueroa MS, Tatomer DC, Wilusz JE. The integrator complex in transcription and development. Trends Biochem Sci 2020;45:923-34.  Back to cited text no. 23
Han KC, Park D, Ju S, Lee YE, Heo SH, Kim YA, et al. Streamlined selection of cancer antigens for vaccine development through integrative multi-omics and high-content cell imaging. Sci Rep 2020;10:5885.  Back to cited text no. 24
Fijak M, Meinhardt A. The testis in immune privilege. Immunol Rev 2006;213:66-81.  Back to cited text no. 25
Fain JS, Van Tongelen A, Loriot A, De Smet C. Epigenetic coactivation of MAGEA6 and CT-GABRA3 defines orientation of a segmental duplication in the human X chromosome. Cytogenet Genome Res 2019;159:12-8.  Back to cited text no. 26
Fain JS, Loriot A, Diacofotaki A, Van Tongelen A, De Smet C. Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer. Sci Rep 2021;11:17346.  Back to cited text no. 27
Endo M, Kanda M, Sawaki K, Shimizu D, Tanaka C, Kobayashi D, et al. Tissue expression of melanoma-associated antigen A6 and clinical characteristics of gastric cancer. Anticancer Res 2019;39:5903-10.  Back to cited text no. 28
Tsang YH, Wang Y, Kong K, Grzeskowiak C, Zagorodna O, Dogruluk T, et al. Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression. Elife 2020;9:e48963.  Back to cited text no. 29
Oh C, Kim HR, Oh S, Ko JY, Kim Y, Kang K, et al. Epigenetic upregulation of MAGE-A isoforms promotes breast cancer cell aggressiveness. Cancers (Basel) 2021;13:3176.  Back to cited text no. 30
Maxfield KE, Taus PJ, Corcoran K, Wooten J, Macion J, Zhou Y, et al. Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nat Commun 2015;6:8840.  Back to cited text no. 31
Sapkota H, Wren JD, Gorbsky GJ. CSAG1 maintains the integrity of the mitotic centrosome in cells with defective p53. J Cell Sci 2020;133:jcs239723.  Back to cited text no. 32
Das B, Senapati S. Functional and mechanistic studies reveal MAGEA3 as a pro-survival factor in pancreatic cancer cells. J Exp Clin Cancer Res 2019;38:294.  Back to cited text no. 33
Chen Y, Zhao H, Li H, Feng X, Tang H, Qiu C, et al. LINC01234/MicroRNA-31-5p/MAGEA3 axis mediates the proliferation and chemoresistance of hepatocellular carcinoma cells. Mol Ther Nucleic Acids 2020;19:168-78.  Back to cited text no. 34
Wang Q, Lu P, Wang T, Zheng Q, Li Y, Leng SX, et al. Sitagliptin affects gastric cancer cells proliferation by suppressing Melanoma-associated antigen-A3 expression through Yes-associated protein inactivation. Cancer Med 2020;9:3816-28.  Back to cited text no. 35
Wu Q, Zhang W, Wang Y, Min Q, Zhang H, Dong D, et al. MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma. Cancer Commun (Lond) 2021;41:1354-72.  Back to cited text no. 36
Soh JE, Abu N, Sagap I, Mazlan L, Yahaya A, Mustangin M, et al. Validation of immunogenic PASD1 peptides against HLA-A*24:02 colorectal cancer. Immunotherapy 2019;11:1205-19.  Back to cited text no. 37
Li R, Guo M, Song L. PAS domain containing repressor 1 (PASD1) promotes glioma cell proliferation through inhibiting apoptosis in vitro. Med Sci Monit 2019;25:6955-64.  Back to cited text no. 38
Kannan A, Philley JV, Hertweck KL, Ndetan H, Singh KP, Sivakumar S, et al. Cancer testis antigen promotes triple negative breast cancer metastasis and is traceable in the circulating extracellular vesicles. Sci Rep 2019;9:11632.  Back to cited text no. 39