Objective  To analyze the value of MEIS1 gene methylation in the early diagnosis of bladder cancer (BCa).

Methods  From August 2023 to May 2024, BCa patients and non-tumor patients in the Harbin Medical University Cancer Hospital were selected as the modeling cohort. Urine and tissue samples were used to analyze the difference of methylation genes in combination with the data in the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to determine the specific methylation markers of BCa. BCa patients and non-tumor patients from June 2024 to October 2024 were selected as the validation cohort, and the diagnostic value of MEIS1 was analyzed by comparing with the pathological gold standard.

Results  A total of 297 subjects were included, including 94 BCa patients and 83 non- tumor patients in the modeling cohort, 90 BCa patients and 30 non-tumor patients in the validation cohort. Analysis of the modeling cohort, TCGA, and GEO data screened out 5 methylation sites, including HOXA9, CRTR, TWIST1, MEIS1, and IFR8. MEIS1 gene was identified as the validation site after further screening conducted based on low methylation background and high degree of differential methylation between adjacent and cancerous tissues (AUC≥0.9). In the validation cohort, the accuracy, sensitivity and specificity of MEIS1 gene methylation in distinguishing BCa patients from normal patients were 89.2%, 91.1% and 83.3%, respectively, and there was no significant difference with the positive detection rate of the gold standard (P>0.05).

Conclusion  MEIS1 gene methylation in urine has important clinical value in non- invasive urine diagnosis of BCa.

1.Compérat E, Amin MB, Cathomas R, et al. Current best practice for bladder cancer: a narrative review of diagnostics and treatments[J]. Lancet, 2022, 400(10364): 1712-1721. DOI: 10.1016/S0140-6736(22)01188-6.

2.Richters A, Aben KKH, Kiemeney LALM. The global burden of urinary bladder cancer: an update[J]. World J Urol, 2020, 38(8): 1895-1904. DOI: 10.1007/s00345-019-02984-4.

3.Jin YH, Zeng XT, Liu TZ, et al. Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition)[J]. Mil Med Res, 2022, 9(1): 44. DOI: 10.1186/s40779-022-00406-y.

4.李志勇,刘卓炜. 上尿路尿路上皮癌的围手术期治疗现状[J]. 中华腔镜泌尿外科杂志(电子版), 2020, 14(5): 326-329. [Li ZY, Liu ZW. Status of perioperative treatment of urothelial carcinoma of upper urinary tract[J]. Chinese Journal of Endourology (Electronic Edition), 2020, 14(5): 326-329.] DOI: 10.3877/cma.j.issn.1674-3253.2020.05.002.

5.Gontero P, Birtle A, Capoun O, et al. European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and Carcinoma In Situ)-a summary of the 2024 guidelines update[J]. Eur Urol, 2024, 86(6): 531-549. DOI: 10.1016/j.eururo.2024.07.027.

6.Ruan W, Chen X, Huang M, et al. A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer[J]. Clin Epigenetics, 2021, 13(1): 91. DOI: 10.1186/s13148-021-01073-x.

7.Wang Z, Chen J, Yang L, et al. Single-cell sequencing-enabled hexokinase 2 assay for noninvasive bladder cancer diagnosis and screening by detecting rare malignant cells in urine[J]. Anal Chem, 2020, 92(24): 16284-16292. DOI: 10.1021/acs.analchem.0c04282.

8.Urabe F, Matsuzaki J, Ito K, et al. Serum microRNA as liquid biopsy biomarker for the prediction of oncological outcomes in patients with bladder cancer[J]. Int J Urol, 2022, 29(9): 968-976. DOI: 10.1111/iju.14858.

9.Lopez-Beltran A, Cheng L, Gevaert T, et al. Current and emerging bladder cancer biomarkers with an emphasis on urine biomarkers[J]. Expert Rev Mol Diagn, 2020, 20(2): 231-243. DOI: 10.1080/14737159.2020.1699791.

10.Li F, Zheng Z, Chen W, et al. Regulation of cisplatin resistance in bladder cancer by epigenetic mechanisms[J]. Drug Resist Updat, 2023, 68: 100938. DOI: 10.1016/j.drup.2023.100938.

11.Meng XY, Shi MJ, Zeng ZH, et al. The role of COL5A2 in patients with muscle-invasive bladder cancer: a bioinformatics analysis of public datasets involving 787 subjects and 29 cell lines[J]. Front Oncol, 2018, 8: 659. DOI: 10.3389/fonc.2018.00659.

12.Lyu XY, Qiang YJ, Zhang B, et al. Identification of immuno-infiltrating MAP1A as a prognosis-related biomarker for bladder cancer and its ceRNA network construction[J]. Front Oncol, 2022, 12: 1016542. DOI: 10.3389/fonc.2022.1016542.

13.Deng LH, Chao HC, Deng HH, et al. A novel and sensitive DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer[J]. BMC Cancer, 2022, 22(1): 510. DOI: 10.1186/s12885-022-09616-y.

14.Tran L, Xiao JF, Agarwal N, et al. Advances in bladder cancer biology and therapy[J]. Nat Rev Cancer, 2021, 21(2): 104-121. DOI: 10.1038/s41568-020-00313-1.

15.胡彬,袁东波,宋具昆,等. TIA1在膀胱癌中的表达及对膀胱癌发生发展和预后的影响[J]. 中华腔镜泌尿外科杂志(电子版), 2021, 15(3): 203-208. [Hu B, Yuan DB, Song  JK, et al. Expression of TIA1 in bladder cancer and its effect on the occurrence, development and prognosis of bladder cancer[J]. Chinese Journal of Endoscopic Urology (Electronic Edition), 2021, 15(3): 203-208.] DOI: 10.3877/cma.j.issn.1674-3253.2021.03.006.

16.Lobo N, Afferi L, Moschini M, et al. Epidemiology, screening, and prevention of bladder cancer[J]. Eur Urol Oncol, 2022, 5(6): 628-639. DOI: 10.1016/j.euo.2022.10.003.

17.Chen X, Zhang J, Ruan W, et al. Urine DNA methylation assay enables early detection and recurrence monitoring for bladder cancer[J]. J Clin Invest, 2020, 130(12): 6278-6289. DOI: 10.1172/JCI139597.

18.Zheng J, Lu S, Huang Y, et al. Preoperative fluorescence in situ hybridization analysis as a predictor of tumor recurrence in patients with non-muscle invasive bladder cancer: a bi-institutional study[J]. J Transl Med, 2023, 21(1): 685. DOI: 10.1186/s12967-023-04528-2.

19.Li Y, Gan Y, Liu J, et al. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer[J]. Signal Transduct Target Ther, 2022, 7(1): 87. DOI: 10.1038/S41392-022-00902-6.

20.Yokoyama T, Nakatake M, Kuwata T, et al. MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis[J]. J Clin Invest, 2016, 126(5): 1664-1678. DOI: 10.1172/JCI81516.

21.Bhanvadia RR, VanOpstall C, Brechka H, et al. MEIS1 and MEIS2 expression and prostate cancer progression: a role for HOXB13 binding partners in metastatic disease[J]. Clin Cancer Res, 2018, 24(15): 3668-3680. DOI: 10.1158/1078-0432.CCR-17-3673.

22.Song F, Wang H, Wang Y. Retraction: myeloid ecotropic viral integration site 1 inhibits cell proliferation, invasion or migration in human gastric cancer[J]. Oncotarget, 2024, 15: 634. DOI: 10.18632/ONCOTARGET.28649.

23.Zhu J, Cui L, Xu A, et al. MEIS1 inhibits clear cell renal cell carcinoma cells proliferation and in vitro invasion or migration[J]. BMC Cancer, 2017, 17(1): 176. DOI: 10.1186/s12885-017-3155-2.

24.Beukers W, van der Keur KA, Kandimalla R, et al. FGFR3, TERT and OTX1 as a urinary biomarker combination for surveillance of patients with bladder cancer in a large prospective multicenter study[J]. J Urol, 2016, 197(6): 1410-1418. DOI: 10.1016/j.juro.2016.12.096.

25.Jubber I, Ong S, Bukavina L, et al. Epidemiology of bladder cancer in 2023: a systematic review of risk factors[J]. Eur Urol, 2023, 84(2): 176-190. DOI: 10.1016/j.eururo.2023.03.029.

26.Kwan ML, Haque R, Young-Wolff KC, et al. Smoking behaviors and prognosis in patients with non-muscle-invasive bladder cancer in the be-well study[J]. JAMA Netw Open, 2022, 5(11): e2244430. DOI: 10.1001/jamanetworkopen.2022.44430.