Department of Urology, National University Health System, Singapore.
Eur Urol. 2011 Mar;59(3):430-7. doi: 10.1016/j.eururo.2010.11.031. Epub 2010 Dec 1.
The natural resistance-associated macrophage protein 1 (NRAMP1) gene is associated with susceptibility to Mycobacterium tuberculosis in humans and to bacillus Calmette-Guérin (BCG) in mice. The detoxification enzyme, human glutathione peroxidase 1 (hGPX1), is associated with recurrence of bladder cancer (BCa).
To determine whether NRAMP1 and hGPX1 gene polymorphisms correlate with response to BCG immunotherapy for non-muscle-invasive BCa (NMIBC).
DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from the peripheral blood of 99 NMIBC patients who were prospectively randomized to receive postresection intravesical BCG (81 mg [n=50] or 27 mg [n=19]) or BCG (27 mg) with interferon alpha (IFN-α; n=30). The median follow-up time was 60 mo.
Intravesical BCG or BCG-IFN-α.
Restriction fragment length polymorphism (RFLP) analysis was performed to identify polymorphisms in the NRAMP1 promoter region (GT repeat number) and at position 543 (aspartate [D] and/or asparagine [N] expression) within the NRAMP1 protein (D543N) and position 198 (proline and/or leucine expression) within the hGPX1 protein (Pro198Leu). Data were analyzed using χ(2) analysis, multivariate analysis, and Kaplan-Meier curves.
On univariate analysis, the NRAMP1 D543N G:G genotype had decreased cancer-specific survival (CSS; p=0.036). The hGPX1 CT genotype (Pro-Leu) had decreased recurrence time (p=0.03) after BCG therapy. On multivariate analysis, patients with the NRAMP1 D543N G:G genotype and allele 3 (GT)n polymorphism had decreased recurrence time (p=0.014 and p=0.03) after BCG therapy. The limitation of this study was its small sample size.
Polymorphisms of the NRAMP1 and hGPX1 genes may be associated with recurrence of BCa after BCG immunotherapy.
自然抗性相关巨噬细胞蛋白 1（NRAMP1）基因与人类对结核分枝杆菌和小鼠对卡介苗（BCG）的易感性有关。解毒酶人谷胱甘肽过氧化物酶 1（hGPX1）与膀胱癌（BCa）的复发有关。
确定 NRAMP1 和 hGPX1 基因多态性是否与非肌层浸润性膀胱癌（NMIBC）对 BCG 免疫治疗的反应相关。
设计、设置和参与者：前瞻性随机分配至接受术后膀胱内 BCG（81mg[50 例]或 27mg[19 例]）或 BCG-干扰素-α（IFN-α；30 例）的 99 例 NMIBC 患者的外周血中获得 DNA。中位随访时间为 60 个月。
膀胱内 BCG 或 BCG-IFN-α。
进行限制性片段长度多态性（RFLP）分析，以鉴定 NRAMP1 启动子区域（GT 重复数）和 NRAMP1 蛋白（D543N）中位置 543（天冬氨酸[D]和/或天冬酰胺[N]表达）以及 hGPX1 蛋白（Pro198Leu）中位置 198（脯氨酸和/或亮氨酸表达）的多态性。使用 χ2 分析、多变量分析和 Kaplan-Meier 曲线进行数据分析。
单变量分析显示，NRAMP1 D543N G：G 基因型的癌症特异性生存（CSS）降低（p=0.036）。BCG 治疗后 hGPX1 CT 基因型（Pro-Leu）的复发时间缩短（p=0.03）。多变量分析显示，NRAMP1 D543N G：G 基因型和等位基因 3（GT）n 多态性的患者在 BCG 治疗后复发时间缩短（p=0.014 和 p=0.03）。本研究的局限性在于样本量小。
NRAMP1 和 hGPX1 基因的多态性可能与 BCG 免疫治疗后 BCa 的复发有关。
