Faculty of Natural Sciences, Vilnius University, Ciurlionio 21, 3101 Vilnius, Lithuania.
J Cancer Res Clin Oncol. 2010 Jun;136(6):847-54. doi: 10.1007/s00432-009-0725-y. Epub 2009 Nov 19.
Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2.
After complete TURB, patients with multifocal superficial BC were treated with five daily intravesical instillations of IL-2. Promoter hypermethylation in six TSGs and the TP53 gene mutations were prospectively assessed by methylation-specific PCR and automated capillary single-strand conformation polymorphism in 21 primary bladder cancer specimens and ten bladder wall biopsies collected during follow-up.
After IL-2 treatment, 9 out of 21 (43%) patients did not develop recurrent tumour within the 1 year of follow-up period. The mean duration of recurrence-free survival in the rest of the study group was 112 days. In the current pilot study, BC with p16 gene hypermethylation had a lower risk of recurrence after treatment with IL-2, as compared to IL-2 treated BC without p16 hypermethylation (p = 0.02). Significant associations were observed between tumour grade and the mean methylation index (p = 0.003), as well as the hypermethylation of the RARbeta gene (p = 0.048).
Our preliminary data suggest that DNA methylation biomarkers may assist in selection of BC patients for efficient IL-2 therapy.
非肌肉浸润性膀胱癌（BC）是一种高度复发性疾病，在经尿道膀胱肿瘤切除术（TURB）后不久就会出现首次复发。白细胞介素 2（IL-2）的局部给药已被证明是 BC 的一种有效辅助治疗方法；然而，缺乏可能识别合适患者亚组的预测生物标志物。在这项初步研究中，我们试图确定接受 IL-2 治疗的 BC 患者中肿瘤抑制基因（TSG）的表观遗传和遗传失活的预后价值。
在完成完全 TURB 后，对多发性浅表 BC 患者采用五次每日膀胱内 IL-2 灌注。在 21 例原发性膀胱癌标本和 10 例膀胱壁活检中，通过甲基化特异性 PCR 和自动毛细管单链构象多态性前瞻性评估了 6 个 TSG 和 TP53 基因突变的启动子甲基化。
在接受 IL-2 治疗后，21 例患者中有 9 例（43%）在 1 年随访期间未出现复发性肿瘤。其余研究组的无复发生存期平均为 112 天。在目前的初步研究中，与未发生 p16 高甲基化的 IL-2 治疗 BC 相比，p16 基因高甲基化的 BC 在接受 IL-2 治疗后复发的风险较低（p=0.02）。还观察到肿瘤分级与平均甲基化指数（p=0.003）以及 RARbeta 基因高甲基化（p=0.048）之间存在显著相关性。
我们的初步数据表明，DNA 甲基化生物标志物可能有助于选择接受有效 IL-2 治疗的 BC 患者。
