Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene
Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene
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DOI：
10.1038/sj.onc.1210131
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发表时间：
2007-05-17
期刊：
影响因子：
8
通讯作者：
Moch, H.
中科院分区：
文献类型：
--
作者：
Zhao, J.;Yart, A.;Moch, H.
编码副纤维蛋白的HRPT2基因失活最近被认为与家族性甲状旁腺功能亢进症颌骨肿瘤综合征有关。患有这种综合征的患者患甲状旁腺和肾脏肿瘤的风险增加。为确定HRPT2与散发性肾肿瘤的相关性，对肾透明细胞癌、乳头状细胞癌、嫌色细胞癌、嗜酸细胞瘤和肾母细胞瘤的HRPT2基因改变进行了分析。HRPT2杂合性缺失(LOH)见于7/56(12.5%)透明细胞、3/14(21%)乳头状肾细胞癌、6/10(60%)嫌色肾细胞癌、3/8(38%)嗜酸细胞瘤和4/10(40%)肾母细胞瘤。此外，在1例透明细胞癌和1例肾母细胞瘤中分别检测到两个新的HRPT2点突变，导致纤维蛋白原K34Q和R292K改变。这些肿瘤显示剩余的野生型等位基因的杂合性缺失，但有趣的是没有von Hippel-Lindau(VHL)突变。功能分析表明，K34Q突变种的副纤维蛋白与野生型蛋白不同，在体内抑制细胞周期蛋白D1的表达存在缺陷。综上所述，这些结果表明，肾癌相关的副纤维蛋白突变发生在没有VHL突变的情况下，这反过来可能导致细胞周期蛋白D1表达的结构性升高和细胞的异常增殖。
Inactivation of the HRPT2 gene encoding parafibromin was recently linked to the familial hyperparathyroidism-jaw tumor syndrome. Patients with this syndrome carry an increased risk of parathyroid and renal tumors. To determine the relevance of HRPT2 for sporadic renal tumors, clear cell, papillary and chromophobe renal cell carcinomas as well as oncocytomas and Wilms tumors were analysed for HRPT2 gene alterations. Loss of heterozygosity (LOH) of HRPT2 was found in seven of 56 (12.5%) clear cell, three of 14 (21%) papillary, six of 10 (60%) chromophobe renal cell carcinomas, three of eight (38%) oncocytomas and four of 10 (40%) Wilms tumors. In addition, two novel HRPT2 point mutations, causing K34Q and R292K changes in parafibromin, were detected in one clear cell carcinoma and one Wilms tumor, respectively. These tumors displayed LOH of the remaining wild-type allele, but interestingly no von Hippel-Lindau (VHL) mutation. Functional analysis revealed that the K34Q mutant species of parafibromin is, unlike wild-type protein, defective in suppressing cyclin D1 expression in vivo. Taken together, these results suggest that renal cancer-associated mutations in parafibromin occur in the absence of VHL mutation, which in turn may contribute to constitutively elevated cyclin D1 expression and abnormal cell proliferation.