SFRP2 Mediates Epstein-Barr Virus and Bladder Cancer Risk: a Mendelian Randomization Study and Colocalization Analysis

Overview

Journal Sci Rep

Specialty Science

Date 2025 Feb 27

PMID 40016549

Authors

Jian Li

Bing Yang

Lei Guo

Wenqi Huang

Qiong Hu

Hongting Yan

Changpu Du

Rong Tan

Dongxin Tang

Affiliations

Soon will be listed here.

Abstract

Studies suggest a possible association between Epstein-Barr virus (EBV) infection and bladder cancer (BCa) risk, though this remains unclear. Secreted frizzled-related protein (sFRP) is also linked to BCa, with some DNA viruses potentially regulating its expression. This study used Mendelian randomization (MR) and colocalization analysis to explore the causal relationship between EBV infection, BCa risk, and the mediating role of sFRP. We first performed a two-sample MR study to assess the causal relationship between 5 EBV-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, ZEBRA) and BCa using the Finnish Consortium's R11 dataset, validated with R10. Reverse MR analysis followed. For significant results, multivariable MR (MVMR) was applied to adjust for confounding risk factors. A two-step MR explored the potential mediating role of 3 sFRPs (sFRP1, sFRP2, sFRP3) between positive exposures and BCa. Colocalization analysis were conducted for positive exposures, mediators, and BCa, with multiple sensitivity analyses confirming the robustness of the results. The two-sample Mendelian randomization study found that EBNA-1 (OR = 1.15, 95% CI: 1.01-1.30; p = 0.039) and VCA-p18 (OR = 1.36, 95% CI: 1.13-1.64; p = 0.001) may increase BCa risk, with only VCA-p18 (P_fdr = 0.006) showing a significant effect after False Discovery Rate (FDR) correction. The Finnish Consortium R10 replication study yielded similar results, and reverse MR analysis did not suggest reverse causality. After MVMR adjusted for relevant confounders, VCA-p18 (OR = 1.40, 95% CI: 1.13-1.74; p = 0.002) still significantly increased BCa risk. Two-step MR identified sFRP2 as a mediator, with VCA-p18 down-regulating sFRP2 expression to elevate BCa risk. Colocalization analysis suggested a shared causal variant (nearby gene HLA-DQA1) between VCA-p18 and BCa (PPH4 = 65.44%). Multiple sensitivity analyses confirmed the robustness of the results. Our study suggests that EBV infection (VCA-p18 antibody) may increase the risk of BCa by lowering sFRP2 levels. Additionally, EBNA-1 antibodies may also contribute to an elevated risk of BCa. We hope these findings will provide new insights for future research on the association between EBV and BCa.

References

Xue H, Shen X, Pan W . Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects. Am J Hum Genet. 2021; 108(7):1251-1269. PMC: 8322939. DOI: 10.1016/j.ajhg.2021.05.014. View

Peng C, Xiao X, Kang B, He S, Li J . Serum secreted frizzled-related protein 5 levels differentially decrease in patients with hepatitis B virus-associated chronic infection and hepatocellular carcinoma. Oncol Lett. 2014; 8(3):1340-1344. PMC: 4114713. DOI: 10.3892/ol.2014.2256. View

Chen J, Xu F, Ruan X, Sun J, Zhang Y, Zhang H . Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses. EBioMedicine. 2023; 89:104494. PMC: 9986512. DOI: 10.1016/j.ebiom.2023.104494. View

Wang X, Wang H, Bu R, Fei X, Zhao C, Song Y . Methylation and aberrant expression of the Wnt antagonist secreted Frizzled-related protein 1 in bladder cancer. Oncol Lett. 2012; 4(2):334-338. PMC: 3402742. DOI: 10.3892/ol.2012.713. View

Dokanei S, Minai-Tehrani D, Moghoofei M, Rostamian M . Investigating the relationship between Epstein-Barr virus infection and gastric cancer: A systematic review and meta-analysis. Health Sci Rep. 2024; 7(3):e1976. PMC: 10948593. DOI: 10.1002/hsr2.1976. View

Wilson J, Bell J, Levine A . Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J. 1996; 15(12):3117-26. PMC: 450254. View

Lu J, Murakami M, Verma S, Cai Q, Haldar S, Kaul R . Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positive B-lymphoma cells through up-regulation of survivin. Virology. 2010; 410(1):64-75. PMC: 4287362. DOI: 10.1016/j.virol.2010.10.029. View

Qu Y, Dang S, Hou P . Gene methylation in gastric cancer. Clin Chim Acta. 2013; 424:53-65. DOI: 10.1016/j.cca.2013.05.002. View

Tsai S, Sheen M, Chen B . Association between HLA-DQA1, HLA-DQB1 and oral cancer. Kaohsiung J Med Sci. 2011; 27(10):441-5. DOI: 10.1016/j.kjms.2011.06.003. View

10.

Chen P, Tsai E, Er T, Chang S, Chen B . HLA-DQA1 and -DQB1 allele typing in southern Taiwanese women with breast cancer. Clin Chem Lab Med. 2007; 45(5):611-4. DOI: 10.1515/CCLM.2007.132. View

11.

Stoehr R, Wissmann C, Suzuki H, Knuechel R, Krieg R, Klopocki E . Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest. 2004; 84(4):465-78. DOI: 10.1038/labinvest.3700068. View

12.

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

13.

Al-Shabanah O, Hafez M, Hassan Z, Sayed-Ahmed M, Abozeed W, Alsheikh A . Methylation of SFRPs and APC genes in ovarian cancer infected with high risk human papillomavirus. Asian Pac J Cancer Prev. 2014; 15(6):2719-25. DOI: 10.7314/apjcp.2014.15.6.2719. View

14.

Leonard S, Wei W, Anderton J, Vockerodt M, Rowe M, Murray P . Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin's lymphoma. J Virol. 2011; 85(18):9568-77. PMC: 3165764. DOI: 10.1128/JVI.00468-11. View

15.

Marsit C, Karagas M, Andrew A, Liu M, Danaee H, Schned A . Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res. 2005; 65(16):7081-5. DOI: 10.1158/0008-5472.CAN-05-0267. View

16.

Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S . Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 2009; 69(7):2766-74. DOI: 10.1158/0008-5472.CAN-08-3070. View

17.

Kosova I, Loran O, Sinyakova L, Gundorova L, Kosov V, Pogodina I . [A prognostic value of level of antiviral antibodies in the development of recurrence of bladder cancer]. Urologiia. 2019; (6):86-94. View

18.

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

19.

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

20.

Rogler A, Hoja S, Socher E, Nolte E, Wach S, Wieland W . Role of two single nucleotide polymorphisms in secreted frizzled related protein 1 and bladder cancer risk. Int J Clin Exp Pathol. 2013; 6(10):1984-98. PMC: 3796220. View