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.

本研究的最初目的是研究胃癌和癌前胃上皮的基因组变化。然而，我们关注的是胃癌的变化，因为我们找不到后者的典型变化。使用覆盖 34 个人胃癌细胞系中 50k SNP 位点的寡核苷酸微阵列对基因拷贝数的变化进行了详尽的评估。在总共 26 个细胞系的 26 个位点发现纯合缺失。拷贝数扩增的情况更为常见，并且在总共 20 个细胞系的 31 个位点中发现了高级别扩增，即至少两个细胞系中超过 5 个拷贝。大约一半的这些基因座以前在胃癌中没有报道过。在这些区域包含的基因中，分别选择10个基因和4个基因用于检查拷贝数扩增和杂合性丢失(LOH)。通过激光显微切割从人胃癌标本中分离出癌组织，并通过实时定量PCR和微卫星标记评估来分析基因的变化，这些变化在人胃癌组织中也很常见。与临床资料比较，拷贝数扩增和LOH多见于有淋巴结转移或血管侵犯的晚期病例。本研究中发现的那些与胃癌相关的基因可能在胃癌发生中发挥作用。此外，I/II 期病例中频繁的 LOH 与较短的总生存期显着相关。确定某些基因的 LOH 可能有助于区分高危患者。