Volume 1,Issue 2
Screening Potential Prognostic Factors for Gastric Carcinoma and Indicators for Tumor Microenvironment Remodeling in Female and Male Patients Based on TCGA Data Mining
The tumor microenvironment (TME) participates largely in the genesis and development of gastric carcinoma (GC). Few studies have focused on the impact of gender on the dynamic modulation of the immune and stromal components in TME. In this paper, the authors used CIBERSORT and the ESTIMATE algorithm to analyze the ratio of tumor infiltrating immune cells (TIC) and the number of immune and stromal components in 221 female and 348 male GC cases from the Cancer Genome Atlas (TCGA) database. The method of COX regression analysis and protein-protein interaction (PPI) network was used to analyze the differentially expressed genes (DEGs). Results showed that the Fc fragment of IgG receptor IIa (FCGR2A, also known as CD32) in females and GDNF family receptor alpha 1 (GFRA1) in males were analyzed as predictive factors by the intersection analysis of univariate COX and PPI. Moreover, FCGR2A was negatively correlated with the survival of female patients, while GFRA1 was positively related to the survival of male patients. Gene Set Enrichment Analysis (GSEA) demonstrated that genes in the FCGR2A high expression group were mainly enriched in the antigen processing and presentation pathway, while genes in the GFRA1 low expression group were mainly enriched in the cell cycle and DNA replication pathway. Furthermore, CIBERSORT analysis for the proportion of TIC revealed that macrophages M2 were positively correlated with FCGR2A expression. And B cells, T cells, monocytes, and macrophages were positively related to GFRA1 expression. The results indicated that the levels of FCGR2A and GFRA1 might be responsible for outlining the prognosis of female and male GC patients, respectively, which highlighted the impact of gender on the tumor progression and offered an extra insight for the therapeutics of GC patients.
[1] Torre LA, Bray F, Siegel RL, et al., 2015, Global Cancer Statistics 2012. A Cancer Journal for Clinicians, 2015(65): 87–
- https://doi.org/10.3322/caac.21262
[2] Waldum HL, Fossmark R, 2018, Types of Gastric Carcinomas. International Journal of Molecular Sciences, 2018(19):
- https://doi.org/10.3390/ijms19124109
[3] Eric VC, Sagaert, X, Topal, B, et al., 2016, Gastric Cancer. The Lancet, 2016(388): 2654–2664. https://doi.org/10.1016/
S0140-6736(16)30354-3
[4] Oliveira C, Pinheiro H, Figueiredo J, et al., 2015, Familial Gastric Cancer: Genetic Susceptibility, Pathology, and
Implications for Management. Lancet Oncology, 2015(16(: 60–70. https://doi.org/10.1016/S1470-2045(14)71016-2
[5] Poorolajal J, Moradi L, Mohammadi Y, et al., 2020, Risk Factors for Stomach Cancer: A Systematic Review and Meta
analysis. Epidemiol Health, 2020(42): e2020004. https://doi.org/10.4178/epih.e2020004
[6] Ladeiras LR, Pereira A, Nogueira A, et al., 2008, Smoking and Gastric Cancer: Systematic Review and Meta-analysis of
Cohort Studies. Cancer Causes Control, 2008(19): 689–701. https://doi.org/10.1007/s10552-008-9132-y
[7] Nanki K, Toshimitsu K, Takano A, et al., 2018, Divergent Routes toward Wnt and R-spondin Niche Independency during
Human Gastric Carcinogenesis. Cell, 2018(174): 856–869. https://doi.org/10.1016/j.cell.2018.07.027
[8] Son B, Lee S, Youn H, et al., 2017, The Role of Tumor Microenvironment in Therapeutic Resistance. Oncotarget, 2017(8):
3933–3945. https://doi.org/10.18632/oncotarget.13907
[9] Ma B, Wells A, Clark AM, 2019, The Pan-therapeutic Resistance of Disseminated Tumor Cells: Role of Phenotypic
Plasticity and the Metastatic Microenvironment. Seminars in Cancer Biology, 2019(60): 138–147. https://doi.org/10.1016/
j.semcancer.2019.07.021
[10] Zhi HZ, Cheng DJ, Jiang Z, et al., 2017, The Prognostic Value and Pathobiological Significance of Glasgow
Microenvironment Score in Gastric Cancer. Journal of Cancer Research and Clinical Oncology, 2017(143): 883–894.
https://doi.org/10.1007/s00432-017-2346-1
[11] Hye WC, Jong BL, 2014, Role of the Tumor Microenvironment in the Pathogenesis of Gastric Carcinoma. World Journal
of Gastroenterology, 2014(20): 1667–1680. https://doi.org/10.3748/wjg.v20.i7.1667
[12] Liu H, Ni S, Wang H, et al., 2020, Charactering Tumor Microenvironment Reveals Stromal‐related Transcription Factors
Promote Tumor Carcinogenesis in Gastric Cancer. Cancer Medicine, 2020(9): 5247–5257. https://doi.org/10.1002/
cam4.3133
[13] Zhang H, Bai M, Deng T, et al., 2016, Cell-derived Microvesicles Mediate the Delivery of miR-29a/c to Suppress
Angiogenesis in Gastric Carcinoma. Cancer Letter, 2016(375): 331–339. https://doi.org/10.1016/j.canlet.2016.03.026
[14] Kasashima H, Yashiro M, Nakamae H, et al., 2017, Clinicopathologic Significance of the CXCL1-CXCR2 Axis in the
Tumor Microenvironment of Gastric Carcinoma. PLOS ONE 2017(12): e0178635. https://doi.org/10.1371/journal.
pone.0178635
[15] Ke WB, Xu GW, Xiao XQ, et al., 2020, BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and
an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining. Frontiers in Oncology,
2020(10): 424. https://doi.org/10.3389/fonc.2020.00424
[16] Peng CW, Liu JY, Yang GF, 2018, The Tumor-stromal Ratio as a Strong Prognosticator for Advanced Gastric Cancer
Patients: Proposal of a new TSNM Staging System. Journal of Gastroenterology, 2018(53): 606–617. https://doi.
org/10.1007/s00535-017-1379-1
[17] Wu X, Gao X, Xing X, et al., 2020, The T-Cell-Inflammation Status Can Predict Outcomes of Adjuvant Chemotherapy
in Patients with Gastric Cancer. Annals of Surgical Oncology, 2020(28): 1407–1416. https://doi.org/10.1245/s10434-020-
09005-4
[18] Wei S, Lu J, Lou J, et al., 2020, Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related
Gene Signatures Associated with Macrophage Infiltration. Frontiers in Genetics, 2020(11): 663. https://doi.org/10.3389/
fgene.2020.00663
[19] Treffers LW, Houdt MV, Bruggeman CW, et al., FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by
Human Neutrophils. Frontiers in Immunology, 2019(9): 3124. https://doi.org/10.3389/fimmu.2018.03124
[20] Viansone AA, Boggiani D, Musolino A, 2018, Prognostic Role of Immunoglobulin G Fragment C Receptor Polymorphisms
in Solid Tumors. JAMA Oncology, 2018(4): 132–133. https://doi.org/10.1001/jamaoncol.2017.2802
[21] Cheung NK, Sowers R, Vickers AJ, 2006, FCGR2APolymorphism is Correlated with Clinical Outcome after
Immunotherapy of Neuroblastoma with Anti-GD2 Antibody and Granulocyte Macrophage Colony-Stimulating Factor.
Journal of Clinical Oncology 2006(24): 2885–2890. https://doi.org/10.1200/jco.2005.04.6011
[22] Zhang W, Gordon M, Schultheis AM, et al., 2007, FCGR2A and FCGR3A Polymorphisms Associated with Clinical
Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated with Single
Agent Cetuximab. Journal of Clinical Oncology 2007(25): 3712–3718. https://doi.org/10.1200/jco.2006.08.8021
[23] Gavin PG, Song N, Kim SR, et al., 2017, Association of Polymorphisms in FCGR2A and FCGR3A with Degree of
Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2–Positive Breast Cancer Analysis of the NSABPB-
31Trial. JAMA Oncology, 2017(3): 335–341 https://doi.org/10.1001/jamaoncol.2016.4884
[24] Erbe AK, Wang W, Goldberg J, et al., 2017, FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell
Carcinoma. Clinical Cancer Research, 2017(23): 2159–2168. https://doi.org/10.1158/1078-0432.ccr-16-1874
[25] Ghesquières H, Cartron G, Seymour JF, et al., 2012, Clinical Outcome of Patients with Follicular Lymphoma Receiving
Chemoimmunotherapy in the PRIMA Study is not Affected by FCGR3A and FCGR2A Polymorphisms. Blood, 2012(120):
2650–2657. https://doi.org/10.1182/blood-2012-05-431825
[26] Xia HZ, Du WD, Wu Q, et al., 2012, E-selectin rs5361 and FCGR2A rs1801274 Variants were Associated with Increased
Risk of Gastric Cancer in a Chinese Population. Molecular Carcinogenesis, 2012(51): 597607. https://doi.org/10.1002/
mc.20828
[27] Mantovani A, Sozzani S, Locati M, 2002, Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for
Polarized M2 Mononuclear Phagocytes. Trends in Immunology, 2002(23): 549–555. https://doi.org/10.1016/S1471-
4906(02)02302-5
[28] Biswas SK, Mantovani A, 2010, Macrophage Plasticity and Interaction with Lymphocyte Subsets: Cancer as a Paradigm.
Nature Immunology, 2010(11): 889–896. https://doi.org/10.1038/ni.1937
[29] Dan H, Liu S, Liu J, et al., RACK1 Promotes Cancer Progression by Increasing the M2/M1 Macrophage Ratio via the NF‐
κB Pathway in Oral Squamous Cell Carcinoma. Molecular Oncology, 2020(14): 795–807. https://doi.org/10.1002/1878-
0261.12644
[30] Vogelpoel LT, Hansen IS, Rispens T, et al., 2014, Fc Gamma Receptor-TLR Cross-talk Elicits Pro-inflammatory Cytokine
Production by Human M2 Macrophages. Nature Communications, 2014(5): 5444. https://doi.org/10.1038/ncomms6444
[31] Peluso MO, Adam A, Armet CM, et al., 2020, The Fully Human Anti-CD47 Antibody SRF231 Exerts Dual-mechanism
Antitumor Activity via Engagement of the Activating Receptor CD32a. The Journal for ImmunoTherapy of Cancer,
2020(8): e000413. https://doi.org/10.1136/jitc-2019-000413
[32] Ibanez CF, Andressoo JO, 2017, Biology of GDNF and its Receptors—Relevance for Disorders of the Central Nervous
System. Neurobiology of Disease, 2017(97): 80–89. https://doi.org/10.1016/j.nbd.2016.01.021
[33] Mihwa K, Dae JK, 2018, GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance.
International Journal of Molecular Sciences, 2018(19): 1078. https://doi.org/10.3390/ijms19041078
[34] Kim M, Jung JY, Choi S, et al., 2017, GFRA1 Promotes Cisplatin-induced Chemoresistance in Osteosarcoma by Inducing
Autophagy. Autophagy, 2017(13): 149–168. https://doi.org/10.1080/15548627.2016.1239676
[35] Picco G, Julien S, Brockhausen I, et al., 2010, Over-expression of ST3Gal-I Promotes Mammary Tumorigenesis.
Glycobiology 2010(20): 1241–1250. https://doi.org/10.1093/glycob/cwq085
[36] Ma WR, Xu P, Liu ZJ, et al., 2020, GFRA1 Impact of Gene Reactivation by DNA Demethylation on Prognosis of Patients
with Metastatic Colon Cancer. World Journal of Gastroenterology, 2020(26): 184–198. https://doi.org/10.3748/wjg.v26.
i2.184