Wnt signaling pathway analysis in renal cell carcinoma in young patients
Wnt signaling pathway analysis in renal cell carcinoma in young patients
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DOI：
10.1038/modpathol.3800957
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发表时间：
2007-12-01
期刊：
影响因子：
7.5
通讯作者：
Koesters, Robert
中科院分区：
文献类型：
--
作者：
Bruder, Elisabeth;Moch, Holger;Koesters, Robert
年轻患者的肾细胞癌在形态学和遗传学上具有异质性。20%属于新发现的Xp11.2易位相关家族，罕见的肿瘤来自肾母细胞瘤。通过β -连环蛋白突变的异常Wnt信号与肾母细胞瘤的发病机制有关，并已发现与WT1突变协同作用。为了表征Wnt信号在年轻患者肾细胞癌中的活性，我们收集了34例年龄小于22岁的患者的肿瘤（3例透明细胞癌，10例Xp11.2易位相关，5例乳头状，2例嫌色，2例集管癌，1例神经母细胞瘤相关，8例未分类肾细胞癌，3例合并肾母细胞瘤）。采用免疫组化方法检测30例肿瘤中β -catenin、其同系物γ -catenin和WT1的表达，并对25例肿瘤中CTNNB1、CTNNG1和WT1基因进行序列分析。2例乳头状癌、1例神经母细胞瘤相关癌和2例肾母细胞瘤引起的癌均有细胞质β -连环蛋白积累。γ -catenin的表达模式与β -catenin相似，但其信号强度在22个肿瘤中较低，在7个肿瘤中相等，仅在1个肿瘤中较强。4例肿瘤显示核WT1表达。一个Xp11.2易位相关的癌表现出罕见的内含子CTNNB1单核苷酸多态性和细胞质β -连环蛋白积累。没有进一步的CTNNB1或CTNNG1序列改变。在肾母细胞瘤引起的癌的肾母细胞瘤成分中发现了WT1突变。这些发现提示Wnt信号通路仅在少数年轻肾细胞癌患者中激活。CTNNB1突变是罕见事件。细胞质β -连环蛋白在Xp11.2相关癌中的积累表明Wnt信号组分与小眼转录因子家族的潜在相互作用也存在于Xp11.2易位癌中。混合型肾细胞癌肾母细胞瘤成分中的WT1突变为这种特殊肿瘤中肾母细胞瘤和癌成分的克隆独立性提供了直接证据。
Renal cell carcinomas in young patients constitute a morphologically and genetically heterogeneous group. Twenty percent belong to the newly recognized Xp11.2 translocation-associated family and rare tumors arise from nephroblastoma. Aberrant Wnt signaling through beta-catenin mutation has been implicated in nephroblastoma pathogenesis and has been found to synergize with WT1 mutations. To characterize Wnt signaling activity in renal cell carcinomas in young patients, we gathered 34 tumors (three clear cell, ten Xp11.2 translocation associated, five papillary, two chromophobe, two collecting duct, one neuroblastoma associated, eight unclassified renal cell carcinomas, and three carcinomas combined with nephroblastoma) from patients less than 22 years. Expression of beta-catenin, its homologue gamma-catenin, and of WT1 was assessed by immunohistochemistry in 30 tumors, and sequence analysis of CTNNB1, CTNNG1, and WT1 genes was performed in 25 tumors. Cytoplasmic beta-catenin accumulation was demonstrated in two papillary carcinomas, one neuroblastoma-associated carcinoma, and two carcinomas arising from nephroblastoma. The pattern of gamma-catenin expression paralleled that of beta-catenin but its signal intensity was lower in 22, equal in 7, and stronger only in 1 tumor, respectively. Four tumors showed nuclear WT1 expression. One Xp11.2 translocation-associated carcinoma presented a rare intronic CTNNB1 single nucleotide polymorphism and cytoplasmic beta-catenin accumulation. There were no further CTNNB1 or CTNNG1 sequence alterations. A WT1 mutation was found in the nephroblastoma component of a carcinoma arising from nephroblastoma. These findings suggest Wnt signaling pathway activation only in a minority of renal cell carcinomas in young patients. CTNNB1 mutations are rare events. Cytoplasmic beta-catenin accumulation in an Xp11.2-associated carcinoma suggests potential interaction of Wnt signaling components with microphthalmia transcription factor family also in Xp11.2 translocation carcinomas. WT1 mutation in the nephroblastoma component of a mixed-type renal cell carcinoma provides direct evidence for clonal independence of nephroblastoma and carcinoma components in this exceptional tumor.