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Exhaustive Studies on Genomic Changes in Gastric Cancer and Precancerous COnditions

关于胃癌和癌前病变的基因组变化的详尽研究

基本信息

批准号：
18590669
负责人：
YOSHIDA Haruhiko
金额：
$ 2.57万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

The original aim of this study was to investigate genomic changes in gastric cancer and precancerous gastric epithelium. However, we focused on the changes in gastric cancer because we could not find changes typical to the latter. Changes in the copy number of genes were exhaustively evaluated with oligonucleotide microarray that covered 50k SNP loci in 34 human gastric cancer cell lines. Homozygous deletion was found at 26 loci in a total of 26 cell lines. Copy number amplification was found much more often, and high-grade amplification, more than five copies in at least two cell lines, was found at 31 loci in a total of 20 cell lines. About one half of these loci were not previously reported in gastric cancer. Among the genes contained in these regions, 10 genes and 4 genes were selected for the examination of copy number amplification and that of loss of heterozygosity (LOH), respectively. Cancer tissue was separated from human gastric cancer specimens by using laser microdissection, and the changes in the genes were analyzed with quantitative real-time PCR and evaluation of microsatellite markers, which were found to be frequent also in human gastric cancer tissues. By comparing with clinical data, copy number amplification and LOH were more frequently found in advanced cases with lymph node metastasis or vascular invasion. Those genes the association of which with gastric cancer was found in the current study may play a role in gastric carcinogenesis. In addition, frequent LOH in cases at Stage I/II was significantly associated with shorter overall survival. Determination of LOH of certain genes may be useful in differentiating high-risk patients.

本研究的最初目的是研究胃癌和癌前胃上皮细胞的基因组变化。然而，我们专注于胃癌的变化，因为我们找不到后者的典型变化。用覆盖50 k个SNP位点的寡核苷酸芯片对34株人胃癌细胞系基因拷贝数的变化进行了详尽的评估。在26个细胞系中发现了26个位点的纯合性缺失。拷贝数扩增被发现更频繁，和高级别的扩增，在至少两个细胞系中超过5个拷贝，被发现在31个位点，在总共20个细胞系。这些位点中约有一半在胃癌中未见报道。在这些区域所包含的基因中，分别选择10个基因和4个基因进行拷贝数扩增和杂合性丢失（洛）检测。采用激光显微切割技术从胃癌组织中分离癌组织，应用实时荧光定量PCR和微卫星标记技术分析胃癌组织中常见的基因变化。与临床资料比较，拷贝数扩增和洛缺失在有淋巴结转移或血管侵犯的晚期病例中更常见。本研究中发现的与胃癌相关的基因可能在胃癌的发生中起作用。此外，I/II期病例中频繁的洛缺失与总生存期缩短显著相关。确定某些基因的洛缺失可能有助于区分高危患者。