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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590669/
• 关键词: Gastric Cancer; Chromosomal Instability; Oligonucleotide Array; Copy Number Amplification; Loss of Heterozygosity; Predictor of Prognosis; 遺伝子コピー数異常; 予後予測; マイクロダイセクション; 胃粘膜上皮細胞; ゲノム解析; ヘリコバクター・ピロリ

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.

这项研究的最初目的是研究胃癌和癌前胃上皮的基因组变化。但是，我们专注于胃癌的变化，因为我们找不到后者典型的变化。用寡核苷酸微阵列对基因拷贝数的变化进行了详尽的评估，该微阵列涵盖了34个人类胃癌细胞系中的50K SNP基因座。在26个基因座中发现了纯合缺失，总共26个细胞系。发现拷贝数扩增的频率要高得多，在至少两个细胞系中，高级扩增，在31个基因座中，总共20个细胞系中发现了五个以上的副本。这些基因座的大约一半以前没有在胃癌中报道。在这些区域中包含的基因中，选择了10个基因和4个基因以检查拷贝数扩增和杂合性丧失（LOH）的基因。通过使用激光显微解剖与人类胃癌标本分离癌症组织，并使用定量的实时PCR分析基因的变化，并评估微卫星标记物，这些标记物在人类胃癌组织中也很常见。通过与临床数据进行比较，在患有淋巴结转移或血管浸润的晚期病例中，拷贝数扩增和LOH更常见。在当前研究中发现的那些基因与胃癌的关联可能在胃癌发生中起作用。此外，在I/II期的情况下，频繁的LOH与较短的总生存期显着相关。确定某些基因的LOH可能对区分高危患者有用。