Identified THBS3 as a risk gene for Gastric Cancer: A Summary Data-Based Mendelian Randomization

Mengyuan Li; Chong Sheng; Xiaoxiao Jia; Xiaoxuan Han; Yunxia Zhang; Kaijuan Wang

doi:10.62051/7g4q7326

Authors

Mengyuan Li
Chong Sheng
Xiaoxiao Jia
Xiaoxuan Han
Yunxia Zhang
Kaijuan Wang

DOI:

https://doi.org/10.62051/7g4q7326

Keywords:

GC; THBS3; eQTL; GWAS; SMR.

Abstract

Gastric cancer (GC) currently ranks as the fourth leading cause of cancer-related deaths worldwide. Genetic variations may influence GC by regulating genes. The aim of this study was to find pleiotropic genes associated with GC risk. Methods: Summary data-based Mendelian Randomization (SMR) is employed to identify genetic variations that are associated with the GC. The Gene interaction network of THBS3 was established through GeneMANIA, and the molecular pathogenesis was elucidated by function and gene set enrichment analysis (GSEA). Furthermore, we conducted bioinformatics analysis using TIMER2.0, TCGA database, and TCIA database to identify the expression signatures, prognosis value, and immune characteristics of the identified gene. SMR analysis of eQTL data from GTEx and CAGE showed that THBS3 showed pleiotropic association with GC risk (CAGE: PSMR = 2.20E-07, PHEIDI = 0.061; GTEx_stomach: PSMR = 1.64E-06, PHEIDI = 0.069). THBS3 and its related genes primarily function through processes such as Extracellular matrix organization, Signaling by PDGF, and Integrin cell surface interactions. The expression of THBS3 is correlated with survival, clinical features, immune cells, and tumor microenvironment. Patients in the low-expression group had better responses to immunotherapy. Our study suggests that THBS3 may play an important role in the occurrence and prognosis of GC and provides a list of prioritized genes for further research on the underlying mechanisms of GC.

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References

[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries [J]. CA Cancer J Clin, 2021, 71(3): 209-49.

[2] 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 [J]. Lancet Gastroenterol Hepatol, 2020, 5(1): 42-54.

[3] YAN C, ZHU M, DING Y, et al. Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations [J]. Gut, 2020, 69(4): 641-51.

[4] ZHU Z, ZHANG F, HU H, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets [J]. Nat Genet, 2016, 48(5): 481-7.

[5] GUSEV A, KO A, SHI H, et al. Integrative approaches for large-scale transcriptome-wide association studies [J]. Nat Genet, 2016, 48(3): 245-52.

[6] LLOYD-JONES L R, HOLLOWAY A, MCRAE A, et al. The Genetic Architecture of Gene Expression in Peripheral Blood [J]. Am J Hum Genet, 2017, 100(2): 228-37.

[7] The GTEx Consortium atlas of genetic regulatory effects across human tissues [J]. Science, 2020, 369(6509): 1318-30.

[8] KURKI M I, KARJALAINEN J, PALTA P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population [J]. Nature, 2023, 613(7944): 508-18.

[9] CHEN X, LIN J, CHEN M, et al. Identification of adhesion-associated extracellular matrix component thrombospondin 3 as a prognostic signature for clear cell renal cell carcinoma [J]. Investig Clin Urol, 2022, 63(1): 107-17.

[10] ADAMS J, LAWLER J. Extracellular matrix: the thrombospondin family [J]. Curr Biol, 1993, 3(3): 188-90.

[11] CHEN X, HUANG Y, WANG Y, et al. THBS4 predicts poor outcomes and promotes proliferation and metastasis in gastric cancer [J]. J Physiol Biochem, 2019, 75(1): 117-23.

[12] WANG X, ZHANG L, LI H, et al. THBS2 is a Potential Prognostic Biomarker in Colorectal Cancer [J]. Sci Rep, 2016, 6: 33366.

[13] MUPPALA S, XIAO R, GAJETON J, et al. Thrombospondin-4 mediates hyperglycemia- and TGF-beta-induced inflammation in breast cancer [J]. Int J Cancer, 2021, 148(8): 2010-22.

[14] DALLA-TORRE C A, YOSHIMOTO M, LEE C H, et al. Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma [J]. BMC Cancer, 2006, 6: 237.

[15] CHEN Y, MENG H, MENG X, et al. Correlation Between Low THBS3 Expression in Peripheral Blood and Acute Myocardial Infarction [J]. Front Biosci (Landmark Ed), 2022, 27(10): 291.

[16] NERSISYAN S, NOVOSAD V, ENGIBARYAN N, et al. ECM-Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer [J]. Front Genet, 2021, 12: 782699.

[17] YAN P, HE Y, XIE K, et al. In silico analyses for potential key genes associated with gastric cancer [J]. PeerJ, 2018, 6: e6092.

[18] SCHIPS T G, VANHOUTTE D, VO A, et al. Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability [J]. Nat Commun, 2019, 10(1): 76.

[19] AUGUSCIAK-DUMA A, LESIAK M, STEPIEN K, et al. mRNA Expression of thrombospondin 1, 2 and 3 from proximal to distal in human abdominal aortic aneurysm - preliminary report [J]. Acta Biochim Pol, 2021, 68(4): 745-50.

[20] LU Y, KONG X, ZHONG W, et al. Diagnostic, Therapeutic, and Prognostic Value of the Thrombospondin Family in Gastric Cancer [J]. Front Mol Biosci, 2021, 8: 647095.

[21] DENG L Y, ZENG X F, TANG D, et al. Expression and prognostic significance of thrombospondin gene family in gastric cancer [J]. J Gastrointest Oncol, 2021, 12(2): 355-64.

[22] BAGHBAN R, ROSHANGAR L, JAHANBAN-ESFAHLAN R, et al. Tumor microenvironment complexity and therapeutic implications at a glance [J]. Cell Commun Signal, 2020, 18(1): 59.

[23] YOSHIHARA K, SHAHMORADGOLI M, MARTINEZ E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data [J]. Nat Commun, 2013, 4: 2612.

[24] PENA-ROMERO A C, ORENES-PINERO E. Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers [J]. Cancers (Basel), 2022, 14(7).

[25] NEGURA I, PAVEL-TANASA M, DANCIU M. Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy [J]. Cancer Treat Rev, 2023, 120: 102629.

[26] CHEN Y, ZHANG S, WANG Q, et al. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein [J]. J Hematol Oncol, 2017, 10(1): 36.

[27] VARRICCHI G, GALDIERO M R, LOFFREDO S, et al. Are Mast Cells MASTers in Cancer? [J]. Front Immunol, 2017, 8: 424.

[28] MIZUKAMI Y, KONO K, KAWAGUCHI Y, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer [J]. Int J Cancer, 2008, 122(10): 2286-93.

[29] QU B, LIU J, PENG Z, et al. CircSOD2 polarizes macrophages towards the M1 phenotype to alleviate cisplatin resistance in gastric cancer cells by targeting the miR-1296/STAT1 axis [J]. Gene, 2023, 887: 147733.

[30] HUANG J, SONG J, LI X, et al. Analysis and prognostic significance of tumour immune infiltrates and immune microenvironment of m6A-related lncRNAs in patients with gastric cancer [J]. BMC Med Genomics, 2022, 15(1): 164.

[31] ZHAO Y, HU S, ZHANG J, et al. Glucoside xylosyltransferase 2 as a diagnostic and prognostic marker in gastric cancer via comprehensive analysis [J]. Bioengineered, 2021, 12(1): 5641-54.

[32] COSTA J J, KEFFER J M, GOFF J P, et al. Aphidicolin-induced proliferative arrest of murine mast cells: morphological and biochemical changes are not accompanied by alterations in cytokine gene induction [J]. Immunology, 1992, 76(3): 413-21.

[33] KINDLUND B, SJOLING A, YAKKALA C, et al. CD4(+) regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-beta [J]. Gastric Cancer, 2017, 20(1): 116-25.

[34] TANAKA A, SAKAGUCHI S. Regulatory T cells in cancer immunotherapy [J]. Cell Res, 2017, 27(1): 109-18.