Germline hepatocyte nuclear factor 1α and 1β mutations in renal cell carcinomas
Germline hepatocyte nuclear factor 1α and 1β mutations in renal cell carcinomas
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DOI：
10.1093/hmg/ddi057
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发表时间：
2005-03-01
影响因子：
3.5
通讯作者：
Zucman-Rossi, J
中科院分区：
文献类型：
--
作者：
Rebouissou, S;Vasiliu, V;Zucman-Rossi, J
肝细胞核因子（HNF）1 α和1 β同源结构域转录因子的一个拷贝中的突变分别使携带者易患3型和5型青年成熟型糖尿病（MODY）。此外，先前在肝细胞腺瘤中HNF 1 α双等位基因失活的鉴定确定了其在肝癌发生中的肿瘤抑制功能。MODY5患者发生卵巢癌，随后发展为嫌色细胞肾细胞癌，这促使我们在一系列20例卵巢肿瘤和35例肾肿瘤中筛查HNF 1 β和HNF 1 α失活。双等位基因HNF 1 β失活被发现在两个12嫌色细胞肾癌的生殖细胞突变和体细胞基因缺失的关联。在这些情况下，PKHD 1（多囊肾和肝病1）和UMOD（尿调蛋白）的表达被关闭，这两个基因由HNF 1 β调节。有趣的是，在13例肾透明细胞癌中的2例中，我们发现了HNF 1 α的单等位基因生殖系突变，而没有相关的靶mRNA表达抑制。在正常和肿瘤肾组织中，我们发现存在一个网络的转录因子差异调节肿瘤亚型。我们确定了两个相关的共调节基因簇，第一组与HNF1 β、PKHD 1和UMOD相关，第二组与HNF1 α、HNF4 α、FABP 1和UGT 2B7相关。最后，这些结果表明，HNF1 β和HNF1 α的生殖系突变可能易患肾肿瘤。此外，我们认为HNF 1 β通过PKHD 1表达调控在嫌色细胞肾细胞癌发生中发挥抑癌基因的作用。
Mutations in one copy of the hepatocyte nuclear factors (HNF) 1alpha and 1beta homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.