Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes
Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes
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DOI：
10.1002/ijc.28013
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发表时间：
2013-07-01
影响因子：
6.4
通讯作者：
Pu, Yeong-Shiau
中科院分区：
文献类型：
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作者：
Chen, Chung-Hsin;Dickman, Kathleen G.;Pu, Yeong-Shiau
马兜铃酸（AA）是所有以马兜铃属为基础的草药的成分，是一种强效肾毒素和与上尿路尿路上皮癌（UUC）相关的人类致癌物。为了研究AA诱导的UUC的临床和病理特征，本研究包括152例UUC患者，其中93例暴露于AA，基于肾皮质中存在马兜铃内酰胺-DNA加合物。基因测序用于鉴定TP 53中具有A：T至T：A颠换的肿瘤，TP 53是与AA相关的突变特征。在TP 53中具有马兜铃内酰胺-DNA加合物和A：T至T：A颠换的病例被定义为AA-UUC，而缺乏这两种生物标志物的患者被归类为非AA-UUC。具有任一生物标志物的病例被分类为可能的AA-UUC。分别有40例（26%）、60例（40%）和52例（34%）患者被分类为AA-UUC、可能AA-UUC和非AA-UUC。AA-UUC患者更年轻（中位年龄：分别为64、68、68岁; p=0.189），主要为女性（分别为65%，42%，35%; p=0.011），有更多的终末期肾病（分别为28%、10%、12%; p=0.055），与可能AA-UUC和非AA-UUC患者相比，为不常吸烟者（分别为5%、22%、33%; p=0.07）。所有14例发生对侧UUC的患者都有马兜铃内酰胺-DNA加合物;其中10例也有特征突变。与可能或非AA-UUC相比，AA-UUC的对侧无UUC生存期较短（分别为p=0.019和0.002），而各组间膀胱癌复发无差异。总之，AA-UUC患者倾向于年轻和女性，并且具有更晚期的肾脏疾病。值得注意的是，AA暴露与发生同步性双侧和异时性对侧UUC的风险增加相关。
Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.