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Abstract：
Background: Bladder cancer (BCa) in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) is a significant concern due to its advanced stage at diagnosis and high mortality rate. Currently, there is a scarcity of specific guidelines for BCa screening in these patients. The development of urine biomarkers for BCa seems to be an attractive non-invasive method of screening or risk stratification in this patient population. DNA methylation is an epigenetic modification, resulting in the transcriptional silencing of tumor suppression genes, that is frequently detected in the urine of BCa patients. Objectives: We aimed to investigate DNA hypermethylation in five gene promoters, previously associated with BCa, in the urine of NLUTD patients, and in comparison with healthy controls. Design, setting and participants: This was a prospective case-control study that recruited neurourology outpatients from a public teaching hospital who had suffered from NLUTD for at least 5 years. They all underwent cystoscopy combined with biopsy for BCa screening following written informed consent. DNA was extracted and DNA methylation was assessed for the RASSF1, RARβ, DAPK, TERT and APC gene promoters via quantitative methylation-specific PCR in urine specimens from the patients and controls. Results: Forty-one patients of mixed NLUTD etiology and 35 controls were enrolled. DNA was detected in 36 patients\' urine specimens and in those of 22 controls. In the urine specimens, DNA was hypermethylated in at least one of five gene promoters in 17/36 patients and in 3/22 controls (47.22% vs. 13.64%, respectively, p = 0.009). RASSF1 was hypermethylated in 10/17 (58.82%) specimens with detected methylation, APC in 7/17 (41.18%), DAPK in 4/17 (23.53%), RAR-β2 in 3/17 (17.56%) and TERT in none. According to a multivariate logistic regression analysis, NLUTD and male gender were significantly associated with hypermethylation (OR = 7.43, p = 0.007 and OR = 4.21; p = 0.04, respectively). In the tissue specimens, histology revealed TaLG BCa in two patients and urothelial squamous metaplasia in five patients. Chronic bladder inflammation was present in 35/41 bladder biopsies. Conclusions: DNA hypermethylation in a panel of five BCa-associated genes in the urine was significantly more frequent in NLUTD patients than in the controls. Our results warrant further evaluation in longitudinal studies assessing the clinical implications and possible associations between DNA hypermethylation, chronic inflammation and BCa in the NLUTD population.
摘要：
背景：患有神经源性下尿路功能障碍（NTUTD）的膀胱癌（BCa）由于其诊断的晚期和高死亡率而受到关注。目前,在这些患者中缺乏BCa筛查的具体指南.BCa尿液生物标志物的开发似乎是该患者人群中筛查或风险分层的有吸引力的非侵入性方法。DNA甲基化是一种表观遗传修饰,导致肿瘤抑制基因的转录沉默，经常在BCa患者的尿液中检测到。目的:我们旨在研究5个基因启动子的DNA甲基化,以前与BCa有关，在NUUTD患者的尿液中，与健康对照相比。设计,背景和参与者:这是一项前瞻性病例对照研究,该研究从一家公立教学医院招募了患有NNUTD至少5年的神经内科门诊患者.在书面知情同意后，他们都接受了膀胱镜检查结合活检进行BCa筛查。提取DNA并评估RASSF1，RARβ，DAPK,TERT和APC基因启动子通过定量甲基化特异性PCR在来自患者和对照的尿液样本中。结果：纳入41例NTUTD病因混合的患者和35例对照。在36例患者的尿液标本和22例对照中检测到DNA。在尿液样本中，在17/36例患者和3/22例对照中，5个基因启动子中的至少一个中DNA被高度甲基化（47.22％vs.13.64%，分别,p=0.009)。10/17（58.82%）标本中RASSF1高甲基化，检测到甲基化，APC在7/17（41.18%），DAPK在4/17（23.53％），RAR-β2在3/17（17.56%），TERT在无。根据多元逻辑回归分析，NNUTD和男性与甲基化显著相关(OR=7.43,p=0.007和OR=4.21;p=0.04)。在组织标本中，组织学检查显示，两名患者为TaLGBCa，五名患者为尿路上皮鳞状化生。慢性膀胱炎症存在于35/41膀胱活检中。结论：NULTD患者尿液中五个BCa相关基因的DNA甲基化明显高于对照组。我们的结果值得在纵向研究中进一步评估，评估DNA超甲基化之间的临床意义和可能的关联，NTUTD人群中的慢性炎症和BCa。
