Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
Eur Urol. 2013 Feb;63(2):364-70. doi: 10.1016/j.eururo.2012.05.050. Epub 2012 Jun 5.
Bacillus Calmette-Guérin (BCG) is a standard treatment to reduce tumor recurrence and delay progression of high-risk non-muscle-invasive (NMI) bladder tumors. However, it is not clear yet which patients are more likely to respond to BCG.
The aim was to evaluate the role of polyamine-modulated factor-1 (PMF-1) methylation in predicting clinical outcome of T1 high-grade (T1HG) bladder tumors treated with BCG.
DESIGN, SETTING, AND PARTICIPANTS: In a retrospective design, PMF-1 methylation was analyzed on tumor specimens belonging to 108 patients with T1HG NMI bladder cancer undergoing BCG treatment. Median follow-up was 77 mo (range: 5-235 mo).
PMF-1 methylation was assessed by methylation-specific polymerase chain reactions. Recurrence, progression into muscle-invasive tumors, and disease-specific survival rates were analyzed using competing risks regression analysis.
Among the 108 patients analyzed, 35 had recurring disease (32.4%), 21 progressed (19.4%), and 16 died of disease (14.8%); 71.3% of tumors had PMF-1 methylation. Univariate analyses using cumulative incidence curves revealed that an unmethylated PMF-1 was significantly associated with increased recurrence (p=0.026), progression (p=0.01), and shorter disease-specific survival (log-rank, p=0.03). Multivariate analyses indicated that among sex, age, focality, tumor size, and concomitant carcinoma in situ, only PMF-1 methylation provided significant hazard ratios (HRs) for recurrence of (HR: 2.032; p=0.042), and progression (HR: 2.910; p=0.020). Limitations of the study include its retrospective design, lymphovascular invasion status not available, short maintenance BCG, and that a second transurethral resection was not performed.
Epigenetic analyses revealed that the methylation status of PMF-1 was associated with the clinical outcome of patients with T1HG tumors undergoing BCG treatment. An unmethylated PMF-1 correlated to recurrence and progression in T1HG disease using univariate and multivariate analyses. Thus, assessing the methylation status of PMF-1 may serve to distinguish patients responding to BCG from those who may require more aggressive therapeutic approaches.
卡介苗（BCG）是一种标准治疗方法，可降低高危非肌肉浸润性（NMI）膀胱癌的肿瘤复发率并延缓进展。然而，目前尚不清楚哪些患者更有可能对 BCG 产生反应。
评估多胺调节因子-1（PMF-1）甲基化在预测接受 BCG 治疗的 T1 高级别（T1HG）膀胱癌患者临床结局中的作用。
设计、地点和参与者：在回顾性设计中，对 108 例接受 BCG 治疗的 T1HG NMI 膀胱癌患者的肿瘤标本进行了 PMF-1 甲基化分析。中位随访时间为 77 个月（范围：5-235 个月）。
通过甲基化特异性聚合酶链反应评估 PMF-1 甲基化。使用竞争风险回归分析分析复发、进展为肌肉浸润性肿瘤以及疾病特异性生存率。
在分析的 108 例患者中，35 例出现疾病复发（32.4%），21 例进展（19.4%），16 例死于疾病（14.8%）；71.3%的肿瘤存在 PMF-1 甲基化。使用累积发生率曲线的单因素分析显示，未甲基化的 PMF-1 与复发（p=0.026）、进展（p=0.01）和疾病特异性生存率缩短（对数秩检验，p=0.03）显著相关。多因素分析表明，在性别、年龄、局灶性、肿瘤大小和同时存在原位癌中，只有 PMF-1 甲基化对复发（HR：2.032；p=0.042）和进展（HR：2.910；p=0.020）提供了显著的危险比（HR）。该研究的局限性包括回顾性设计、无法获得淋巴血管侵犯状态、维持性 BCG 时间短以及未进行第二次经尿道膀胱肿瘤切除术。
表观遗传学分析表明，PMF-1 的甲基化状态与接受 BCG 治疗的 T1HG 肿瘤患者的临床结局相关。未甲基化的 PMF-1 与 T1HG 疾病的复发和进展相关，这在单因素和多因素分析中均得到证实。因此，评估 PMF-1 的甲基化状态可能有助于区分对 BCG 有反应的患者和可能需要更积极治疗方法的患者。
