Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: evidence for Wnt pathway implication
Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: evidence for Wnt pathway implication
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DOI：
10.1002/ijc.23917
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发表时间：
2009-01-01
影响因子：
6.4
通讯作者：
Bamias, Aristotle
中科院分区：
文献类型：
--
作者：
Kastritis, Efstathios;Murray, Samuel;Bamias, Aristotle
Wnt通路信号传导在许多癌症中是至关重要的，并且数据表明与其他关键癌症通路的串扰，然而在尿路上皮癌发生中，它尚未被广泛研究。我们寻找腺瘤性结肠息肉病（APC）的突变，这是该通路的关键调节因子，并研究了侵袭性尿路上皮癌患者中b-连环蛋白表达及其与其他凋亡、血管生成和增殖标志物表达的相互作用。直接测序70例肌肉浸润性疾病患者的APC突变簇区域，这些患者接受了手术和辅助化疗。采用免疫组织化学方法研究了考克斯-2、p53、Ki 67和b-连环蛋白，并通过CD 105表达定量了微血管密度。单体细胞氨基酸取代（错义）被发现在9（13%）和移码缺失2（3%）肿瘤，所有位于邻近区域的b-连环蛋白结合位点。有APC错义突变或b-连环蛋白核积聚的患者考克斯-2过表达频率较低（24% vs. 76%，p = 0.1143），淋巴结受累频率较高（75% vs. 38%，p = 0.023）。APC突变或b-连环蛋白积聚的患者无病期较短（13.4 vs. 28个月，p = 0.07），而在多变量分析中，他们的疾病特异性生存期较短（60.5 vs. 20.6个月，p = 0.048）。体细胞APC错义突变在晚期尿路上皮肿瘤中并不罕见。APC突变和/或b-连环蛋白的异常表达与不良结局相关。需要进一步研究Wilt通路的作用，与其他通路的潜在串扰以及尿路上皮癌的潜在候选治疗靶点。(C)2008 Wiley-Liss，Inc.
Wnt pathway signaling is crucial in many cancers and data indicate crosstalk with other key cancer pathways, however in urothelial carcinogenesis it has not been extensively studied. We searched for mutations in adenomatous polyposis coli (APC), a key regulator of the pathway, and studied b-catenin expression and interactions with the expression of other markers of apoptosis, angiogenesis, and proliferation in patients with invasive urothelial cancer. The mutation cluster region of APC was directly sequenced in 70 patients with muscle invasive disease who were treated with surgery and adjuvant chemotherapy. COX-2, p53, Ki67, and b-catenin were studied immunohistochemically and micro vessel density was quantified by CD105 expression. Single Somatic amino-acid substitutions (missense) were found in 9 (13%) and frameshift deletions in 2 (3%) tumors, all located in regions adjacent to b-catenin binding sites. Patients having either APC missense mutations or b-catenin nuclear accumulation had less frequent COX-2 overexpression (24% vs. 76%, p = 0.1143) and more frequent lymph node involvement (75% vs. 38%, p = 0.023). Patients with either APC mutations or b-catenin accumulation had shorter disease-free interval (13.4 vs. 28 months, p = 0.07), whereas in multivariate analysis they hall shorter disease-specific survival (60.5 vs. 20.6 months, p = 0.048). Somatic APC missense mutations are not rare in advanced urothelial neoplasms. Either APC mutations and/or aberrant expression of b-catenin are associated with worse outcome. Further study of the role of the Wilt pathway, potential crosstalk with other pathways and potential candidate therapeutic targets in urothelial cancer is needed. (C) 2008 Wiley-Liss, Inc.