Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33
Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33
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DOI：
10.1006/geno.1997.5165
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发表时间：
1998-03-15
期刊：
影响因子：
4.4
通讯作者：
Knowles, MA
中科院分区：
文献类型：
--
作者：
Habuchi, T;Luscombe, N;Knowles, MA
9号染色体上的杂合性缺失（洛）是膀胱移行细胞癌（TCC）中最常见的遗传变异，表明存在一个或多个相关的肿瘤抑制基因。我们以前映射这些推定的肿瘤抑制基因座之一，9 q32-q33和本地化的候选区域内的一个单一的YAC 840 kb的大小。该基因座已被命名为DBC 1（膀胱癌基因1中缺失）。我们已经确定了一个新的基因，DBCCR 1，在这个候选区域通过搜索表达序列标签（EST），映射到跨越该地区的YAC。使用整个DBCCR 1 cDNA序列进行数据库搜索，发现了几个人类EST和一些同源小鼠EST。然而，预测的761个氨基酸的序列没有显着的同源性，已知的蛋白质序列。编码区的突变分析和Southern印迹分析在原发性TCC中既没有检测到体细胞突变也没有检测到总体遗传改变。尽管DBCCR 1在包括尿道癌在内的多种正常人体组织中表达，但在10个膀胱癌细胞系中的5个（50%）中不表达mRNA。对该基因5'端CpG岛的甲基化分析和去甲基化剂诱导的从头表达表明，该岛可能是高甲基化的常见靶点，并且基于高甲基化的基因沉默发生在TCC中。这些发现使DBCCR 1成为DBC 1的良好候选者。(C)北京：科学出版社.
Loss of heterozygosity (LOH) on chromosome 9q is the most frequent genetic alteration in transitional cell carcinoma (TCC) of the bladder, indicating the presence of one or more relevant tumor suppressor genes. We previously mapped one of these putative tumor suppressor loci to 9q32-q33 and localized the candidate region within a single YAC 840 kb in size. This locus has been designated DBC1 (for deleted in bladder cancer gene 1). We have identified a novel gene, DBCCR1, in this candidate region by searching for expressed sequence tags (ESTs) that map to YACs spanning the region. Database searching using the entire DBCCR1 cDNA sequence identified several human ESTs and a few homologous mouse ESTs. However, the predicted 761-amino-acid sequence had no significant homology to known protein sequences. Mutation analysis of the coding region and Southern blot analysis detected neither somatic mutations nor gross genetic alterations in primary TCCs. Although DBCCR1 was expressed in multiple normal human tissues including urothelium, mRNA expression was absent in 5 of 10 (50%) bladder cancer cell lines. Methylation analysis of the CpG island at the 5' region of the gene and the induction of de novo expression by a demethylating agent indicated that this island might be a frequent target for hypermethylation and that hypermethylation-based silencing of the gene occurs in TCC. These findings make DBCCR1 a good candidate for DBC1. (C) 1998 Academic Press.