Progress of urinary circulating tumor DNA in the early diagnosis and therapeutic monitoring of bladder cancer
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摘要: 膀胱癌(bladder cancer，BC)是世界上最常见的癌症类型之一，也是最致命的泌尿系统恶性肿瘤。目前，BC的诊断和随访依赖于膀胱镜检查和细胞学方法，具有侵入性且往往受到肿瘤异质性的影响。因此，发现新的预测性生物标志物对BC的诊断、进展和预后至关重要。已有研究显示，尿液循环肿瘤DNA(circulating tumor DNA，ctDNA)与肿瘤细胞具有同源性，相比于血浆ctDNA具有更高的浓度，可能对泌尿系统肿瘤的早期检出发挥作用。但样本量较小且分离难度较高，检测方法的标准化仍需进一步统一。本文总结了尿液ctDNA作为液体生物标志物在BC早期诊断、疗效监控及复发预测方面的价值，以为临床提供参考。Abstract: Bladder cancer(BC) is one of the most common types of cancer in the world and the most lethal urological malignancy. Currently, the diagnosis and follow-up of BC rely on cystoscopy and cytological methods, which are invasive and often affected by tumor heterogeneity. Therefore, the discovery of new predictive biomarkers is crucial for the diagnosis, progression and prognosis of BC. It has been shown that urinary circulating tumor DNA(ctDNA) is homologous to tumor cells, with higher concentrations compared to plasma ctDNA, so it may be useful for early detection of urological tumors. However, the sample size is small and difficult to isolate, and the standardization of detection methods still needs further harmonization. This paper summarizes the value of urinary ctDNA as a liquid biomarker for early diagnosis, efficacy monitoring and recurrence prediction in BC so as to provide clinical reference.
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Key words:
- urinary circulating tumor DNA /
- circulating tumor DNA /
- bladder cancer
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表 1 尿液ctDNA检测技术的方法及优缺点
技术名称 方法 优点 限制性 磁珠捕获法(BEAMING技术) 结合了dPCR和流式细胞术，将不同类别的磁珠分布在对应的DNA中，利用磁珠吸附DNA，然后用流式细胞仪检测标记以计算出ctDNA 允许极其精确地计数携带感兴趣的突变的总模板分子的数目，并且可以实现低至0.01%的检测限度具有较高的灵敏度与精确性 低通量不能检测未知突变 NGS 第二代高通量测序法，对单个样本中的数亿个DNA片段进行大规模并行测序 高灵敏度(某些方法)比其他NGS方法便宜 不如其他NGS方法全面无法检测体细胞拷贝数改变(SCNAs) 癌症个体化深度测序分析方法(CAPP-Seq) 基于NGS技术通过深度测序来研究ctDNA特性 可以同时覆盖数千个不同的基因组区域不需要事先了解肿瘤的突变具有非常高的分析灵敏度 比基于扩增子的方法更耗时只能检测所覆盖的基因组区域中的改变。 数字微滴式聚合酶链反应(ddPCR) 通过对目标基因进行筛选，检测特定基因突变，从而发现微小残留病灶 可针对性检测尿液DNA中的特定突变不依赖CT值，对低丰度突变具有高灵敏度有助于早期和高度敏感地检测疾病复发 受限于捕获的突变数量少并且不适应肿瘤异质性和随时间的分子进化 
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[1] Spiess PE, Agarwal N, Bangs R, et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2017, 15(10): 1240-1267. doi: 10.6004/jnccn.2017.0156
[2] Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis[J]. Urology, 2005, 66(6 Suppl 1): 4-34.
[3] Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses[J]. Urology, 2003, 61(1): 109-118. doi: 10.1016/S0090-4295(02)02136-2
[4] Avritscher EB, Cooksley CD, Grossman HB, et al. Clinical model of lifetime cost of treating bladder cancer and associated complications[J]. Urology, 2006, 68(3): 549-553. doi: 10.1016/j.urology.2006.03.062
[5] Markus H, Zhao J, Contente-Cuomo T, et al. Analysis of recurrently protected genomic regions in cell-free DNA found in urine[J]. Sci Transl Med, 2021, 13(581): eaaz3088. doi: 10.1126/scitranslmed.aaz3088
[6] Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA[J]. Cancer Discov, 2014, 4(6): 650-661. doi: 10.1158/2159-8290.CD-13-1014
[7] 邹文超, 陈南辉. 晚期膀胱癌免疫治疗潜在的生物标志物研究进展[J]. 临床泌尿外科杂志, 2023 38(1): 72-77. https://lcmw.whuhzzs.com/article/doi/10.13201/j.issn.1001-1420.2023.01.016
[8] Nassar AH, Umeton R, Kim J, et al: Mutational analysis of 472 urothelial carcinoma across grades and anatomic sites[J]. Clin Cancer Res, 2019, 25: 2458-2470. doi: 10.1158/1078-0432.CCR-18-3121
[9] Mouliere F, Robert B, Arnau Peyrotte E, et al. High fragmentation characterizes tumour-derived circulating DNA[J]. PLoS One, 2011, 6(9): e23418. doi: 10.1371/journal.pone.0023418
[10] Mouliere F, Thierry AR. The importance of examining the proportion of circulating DNA originating from tumor, microenvironment and normal cells in colorectal cancer patients[J]. Expert Opin Biol Ther, 2012, 12 Suppl 1: S209-S215.
[11] Udayan G, Marsella A, Valentini P. An ultrasensitive colorimetric test for the detection of somatic rare mutations in DNA[J]. Nanoscale, 2020, 12(5): 2973-2979. doi: 10.1039/C9NR10030J
[12] Liao H, Li H. Advances in the Detection Technologies and Clinical Applications of Circulating Tumor DNA in Metastatic Breast Cancer[J]. Cancer Manag Res, 2020, 12: 3547-3560. doi: 10.2147/CMAR.S249041
[13] García Moreira V, Prieto García B, de la Cera Martínez T, et al: Elevated transrenal DNA(cell-free urine DNA)in patients with urinary tract infection compared to healthy controls[J]. Clin Biochem, 2009, 42(7-8): 729-731. doi: 10.1016/j.clinbiochem.2008.12.021
[14] Goto T, Hirotsu Y, Amemiya K, et al. Distribution of circulating tumor DNA in lung cancer: analysis of the primary lung and bone marrow along with the pulmonary venous and peripheral blood[J]. Oncotarget, 2017, 8(35): 59268-59281. doi: 10.18632/oncotarget.19538
[15] Ge G, Peng D, Guan B, et al. Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing[J]. Clin Chem, 2020, 66(1): 188-198. doi: 10.1373/clinchem.2019.309633
[16] Dudley JC, Schroers-Martin J, Lazzareschi DV, et al. Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA[J]. Cancer Discov, 2019, 9(4): 500-509. doi: 10.1158/2159-8290.CD-18-0825
[17] Hirotsu Y, Yokoyama H, Amemiya K, et al. Genomic profile of urine has high diagnostic sensitivity compared to cytology in non-invasive urothelial bladder cancer[J]. Cancer Sci, 2019, 110(10): 3235-3243. doi: 10.1111/cas.14155
[18] Togneri FS, Ward DG, Foster JM, et al. Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA[J]. Eur J Hum Genet, 2016, 24(8): 1167-1174. doi: 10.1038/ejhg.2015.281
[19] Russo IJ, Ju Y, Gordon NS, et al. Toward Personalised Liquid Biopsies for Urothelial Carcinoma: Characterisation of ddPCR and Urinary cfDNA for the Detection of the TERT 228G>A/T Mutation[J]. Bladder Cancer, 2018, 4(1): 41-48. doi: 10.3233/BLC-170152
[20] Hayashi Y, Fujita K, Matsuzaki K, et al. Clinical Significance of Hotspot Mutation Analysis of Urinary Cell-Free DNA in Urothelial Bladder Cancer[J]. Front Oncol, 2020, 10: 755. doi: 10.3389/fonc.2020.00755
[21] Ou Z, Li K, Yang T, et al. Detection of bladder cancer using urinary cell-free DNA and cellular DNA[J]. Clin Transl Med, 2020, 9(1): 4. doi: 10.1186/s40169-020-0257-2
[22] Wu S, Zheng J, Li Y, et al. Development and Validation of an MRI-Based Radiomics Signature for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer[J]. EBio Medicine, 2018, 34: 76-84.
[23] Christensen E, Birkenkamp-Demtröder K, Nordentoft I, et al. Liquid Biopsy Analysis of FGFR3 and PIK3CA Hotspot Mutations for Disease Surveillance in Bladder Cancer[J]. Eur Urol, 2017, 71(6): 961-969. doi: 10.1016/j.eururo.2016.12.016
[24] Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma[J]. J Clin Oncol, 2019, 37(18): 1547-1557. doi: 10.1200/JCO.18.02052
[25] Kinde I, Munari E, Faraj SF, et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine[J]. Cancer Res, 2013, 73(24): 7162-7167. doi: 10.1158/0008-5472.CAN-13-2498
[26] Sung JY, Sun JM, Chang Jeong B, et al. FGFR3 overexpression is prognostic of adverse outcome for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy[J]. Urol Oncol, 2014, 32(1): 49. e23-e31.
[27] Foth M, Ismail NFB, Kung JSC, et al. FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation[J]. J Pathol, 2018, 246(3): 331-343. doi: 10.1002/path.5143
[28] Chauhan PS, Chen K, Babbra RK, et al. Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study[J]. PLoS Med, 2021, 18(8): e1003732. doi: 10.1371/journal.pmed.1003732
[29] Patel KM, van der Vos KE, Smith CG, et al: Association of plasma and urinary mutant DNA with clinical outcomes in muscle invasive bladder cancer[J]. Sci Rep, 2017, 7: 5554. doi: 10.1038/s41598-017-05623-3
[30] Birkenkamp-Demtröder K, Christensen E, Nordentoft I, et al. Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis[J]. Eur Urol, 2018, 73(4): 535-540. doi: 10.1016/j.eururo.2017.09.011
[31] Raja R, Kuziora M, Brohawn PZ, et al. Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab[J]. Clin Cancer Res, 2018, 24(24): 6212-6222. doi: 10.1158/1078-0432.CCR-18-0386
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