RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors
RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors
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DOI：
10.1158/0008-5472.can-05-1647
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发表时间：
2005-10-15
期刊：
影响因子：
11.2
通讯作者：
Bae, SC
中科院分区：
文献类型：
--
作者：
Kim, WJ;Kim, EJ;Bae, SC
RUNX 3在许多肿瘤中以高频率失活。然而，在大多数情况下，失活是由启动子超甲基化引起的基因沉默引起的。由于已知表观遗传沉默会影响癌细胞中的许多主要肿瘤抑制基因，因此尚不清楚RUNX 3是否主要负责这些病例中的致癌诱导，除了我们先前报道的胃癌病例。我们研究了124例膀胱肿瘤病例和7个膀胱肿瘤衍生细胞系中RUNX 3的遗传和表观遗传改变。在这里，我们发现RUNX 3在73%（90/124）的原发性膀胱肿瘤标本和86%（6/7）的膀胱肿瘤细胞系中因异常DNA甲基化而失活。而20例正常膀胱粘膜的启动子区均未甲基化。重要的是，一名患者携带错义突变，每一个都导致高度保守的Runt结构域中的氨基酸取代。这些突变消除了RUNX 3的DNA结合能力。第二名患者在Runt结构域编码区内有一个单核苷酸缺失，导致蛋白质截短。RUNX 3甲基化是膀胱肿瘤发生、浅表膀胱肿瘤复发和随后肿瘤进展的重要风险因素。这些结果强烈表明，RUNX 3的失活可能有助于膀胱肿瘤的发展，并且RUNX 3的启动子甲基化和沉默可能是膀胱肿瘤复发和进展的有用预后标志物。
RUNX3 is inactivated at high frequency in many tumors. However, in most cases, inactivation is caused by silencing of the gene due to promoter hypermethylation. Because epigenetic silencing is known to affect many major tumor suppressor genes in cancer cells, it is not clear whether RUNX3 is primarily responsible for the induction of carcinogenesis in these cases, except for the gastric cancer cases that we reported previously. We investigated genetic and epigenetic alterations of RUNX3 in 124 bladder tumor cases and seven bladder tumor-derived cell lines. Here we show that RUNX3 is inactivated by aberrant DNA methylation in 73% (90 of 124) of primary bladder tumor specimens and 86% (six of seven) of bladder tumor cell lines. In contrast, the promoter regions of 20 normal bladder mucosae were unmethylated. Importantly, one patient bore missense mutations, each of which resulted in amino acid substitutions in the highly conserved Runt domain. The mutations abolished the DNA-binding ability of RUNX3. A second patient had a single nucleotide deletion within the Runt domain coding region that resulted in truncation of the protein. RUNX3 methylation was a significant risk factor for bladder tumor development, superficial bladder tumor recurrence, and subsequent tumor progression. These results strongly suggest that inactivation of RUNX3 may contribute to bladder tumor development and that promoter methylation and silencing of RUNX3 could be useful prognostic markers for both bladder tumor recurrence and progression.