Section of Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Clin Cancer Res. 2010 Apr 1;16(7):2036-45. doi: 10.1158/1078-0432.CCR-09-2890. Epub 2010 Mar 23.
Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP).
We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation-dependent Probe Amplification, or fluorescence in situ hybridization.
We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in approximately 4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%).
Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor.
Wilms 瘤（WT）是最常见的小儿肾恶性肿瘤，与几个特征明确的基因的突变有关，尤其是 WT1、CTNNB1、WTX 和 TP53。然而，大多数病例并不携带这些基因的突变。我们假设肿瘤行为的其他驱动因素将包含在一致的基因组拷贝数变化区域内，特别是那些与国际小儿肿瘤学会（SIOP）定义的 WT 风险组相关的区域。
我们分析了根据 SIOP 方案治疗的选定风险组中 100 多个肿瘤的高分辨率（Affymetrix 250K 单核苷酸多态性芯片）基因组拷贝数谱，进一步通过测序、多重连接依赖性探针扩增或荧光原位杂交对感兴趣的基因进行特征描述。
我们确定了 FBXW7，一种 E3 泛素连接酶成分，作为一种新的 Wilms 瘤基因，在检查的肿瘤中约有 4%发生突变或缺失。引人注目的是，14 例新辅助化疗后上皮型组织学的肿瘤中有 3 例（21%）存在 FBXW7 异常，而第四例 WT 患者的 FBXW7 和 WT1 均存在种系突变。我们还表明，在 104 例（8.7%）病例中检测到的 MYCN 拷贝数增益在 WT 中相对常见，在高风险弥漫性间变性亚型的肿瘤中更为常见（19 例中的 6 例，32%）。
由于 MYCN 本身是 FBXW7 介导的泛素化和降解的靶标，这些结果表明，不同 WT 亚型通过不同机制失调了一个共同途径。针对 MYCN 的新兴疗法在几种其他儿科癌症中也被扩增，因此可能对高危 Wilms 瘤有价值。
