Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events
Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events
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DOI：
10.1002/ijc.25651
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发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Guldberg, Per
中科院分区：
文献类型：
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作者：
Serizawa, Reza R.;Ralfkiaer, Ulrik;Guldberg, Per
膀胱癌基因组含有许多致癌突变和异常甲基化的基因启动子。我们研究的目的是生成这些改变的概况，并研究它们作为尿沉积物中的生物标志物用于膀胱癌的非侵入性检测的用途。我们系统地筛查了FGFR 3、PIK 3CA、TP 53、HRAS、NRAS和KRAS的突变，并在来自118名膀胱肿瘤患者的一系列前瞻性肿瘤活检（N = 105）和尿液样本（N = 113）中定量评估了APC、ARF、DBC 1、INK 4A、RARB、RASSF 1A、SFRP 1、SFRP 2、SFRP 4、SFRP 5和WIF 1的甲基化状态。我们还分析了33例非癌性尿路病变患者的尿液样本。在105例肿瘤活检中共检测到95个致癌突变和189个超甲基化事件。总的标志物组提供了93%的灵敏度，而突变和甲基化标志物单独提供的灵敏度分别为72%和70%。在尿液样本中，所有标记物的灵敏度为70%，突变标记物为50%，甲基化标记物为52%。FGFR 3突变在没有甲基化事件的肿瘤中比在有一个或多个甲基化事件的肿瘤中更频繁地发生（78% vs. 33%; p < 0.0001）。FGFR 3突变与三种甲基化标志物（APC、RASSF 1A和SFRP 2）的组合在肿瘤中提供了90%的灵敏度，在尿液中提供了62%的灵敏度和100%的特异性。这些结果表明FGFR 3突变和高甲基化事件之间存在负相关性，这可能用于改善膀胱癌的非侵入性，基于DNA的检测。
The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA-based detection of bladder cancer.