Zhang Lei, Xiong Gengyan, Fang Dong, Li Xuesong, Liu Jin, Ci Weimin, Zhao Wei, Singla Nirmish, He Zhisong, Zhou Liqun
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China.
Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
J Exp Clin Cancer Res. 2015 Jan 22;34(1):5. doi: 10.1186/s13046-015-0120-2.
Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients.
In a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3-144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence.
Thirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2-139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.
Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.
基因的异常甲基化是尿路上皮癌发生过程中最常见的表观遗传修饰之一。然而，甲基化对根治性肾输尿管切除术（RNU）后对侧新发上尿路尿路上皮癌（UTUC）的预测作用尚不清楚。我们回顾性研究了DNA甲基化及其他临床病理因素在一个大型单中心队列患者根治性肾输尿管切除术（RNU）后对侧上尿路尿路上皮癌（UTUC）复发中的预测作用。
采用回顾性设计，对664例因原发性UTUC接受RNU治疗的连续患者的肿瘤标本进行10个基因的甲基化分析。中位随访时间为48个月（范围：3 - 144个月）。通过甲基化敏感聚合酶链反应检测基因甲基化，并计算甲基化指数（MI），以反映甲基化程度。采用对数秩检验和Cox回归来确定对侧UTUC复发的预测因素。
中位随访27.5个月（范围：2 - 139个月）后，30例（4.5%）患者发生了后续对侧UTUC。88.9%的UTUC存在至少一个基因启动子位点的启动子甲基化。与无对侧复发的肿瘤相比，对侧UTUC复发的肿瘤中甲基化较少且MI较低（P = 0.001）。高MI（P = 0.007）与较差的癌症特异性生存率显著相关。多变量分析表明，未甲基化的RASSF1A（P = 0.039）、对侧UTUC之前无膀胱复发（P = 0.009）、肾移植史（P < 0.001）以及术前肾功能不全（P = 0.002）是RNU后对侧UTUC复发的独立危险因素。
我们的数据表明DNA甲基化在预测RNU后对侧UTUC复发中具有潜在作用。这些信息有助于识别RNU后有对侧新发UTUC复发高风险的患者，他们在随访期间需要密切监测。
