Identification of novel oncogenes invloved in onset and progression of cancers with poor prognosis.

鉴定与预后不良的癌症的发生和进展有关的新癌基因。

基本信息

批准号：
09670145
负责人：
UCHIDA Kazuhiko
金额：
$ 1.92万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670145/
关键词：
biliary tract cancer ovarian cancer neuroblastoma gastric cancer DNA microarray array CGH prognosis 1q23 amplification 難治がん浸潤転移マイクロアレイ難治癌遺伝子 CGH 胆道癌卵巣癌

项目摘要

(1997) In spite of the development of clinical techniques, the prognoses of many cancers are still poor. Comparative genomic hybridization (CGH) is useful for identification of novel oncogenes and tumor suppressor genes involved in the carcinogenesis. 1) Biliary tract cancer ; CGH was performed on 30 fresh frozen tissues of gallbladder cancers. Chromosomal gain of 12p was associated with stage III and IV (P<0.05). Therefore, gain of 12p may be a potential prognostic factor of gallbladder cancers. 2) Ovarian cancer ; In order to find genetic changes in drug-resistant tumors, CGH was performed on 21 primary ovarian cancers and some cell lines. We found gains in chromosomal regions 1p, 1q and 19p, and losses in 2p and 15q to be related to the cisplatin-resistant phenotype. The cell lines which acquired the taxol-resistance had chromosomal gain of 7q where MDR gene was located. The amplification of MDR gene was confirmed by southern blot analysis. Present findings suggest that these chromo … More somal gains and losses may be potential indicators for prediction of resistance in ovarian cancer patients before cisplatin- and/or taxol-based chemotherapy. 3) Neuroblastoma ; We performed CGH on 24 neuroblastomas and dual-color FISH to identify genetic aberrations associated with progressive neuroblastoma. A novel chromosomal gain at 1q21-q25 was found in all of progressive stage 4 neuroblastomas. Furthermore, by FISH analysis using cosmid clones, the 1q21-q25 gain was narrowed to 1q23. These results suggest that DNA amplification at 1q23 may play a role in the development of progressive neuroblastoma in advanced stage.(1998) To clarify the biological characteristics of regressive and progressive neuroblastomas, CGH was performed on 67 patients with neuroblastomas. The CGH data of all regressive tumors (stage1-3 and 4s) revealed whole-chromosome aberrations of whole portion of chromosome. On the other hand, progressive tumors revealed chromosomal gains and losses on regional portion of chromosome. Our data suggest that neuroblastomas are classified into two biologically different groups, one of which displays progressive disease which displays progressive disease which has partial chromosomal changes, whereas the other mimics advanced stage 3/4 neuroblastoma but displays regressive disease which has whole chromosomal aberrations.(1999) Recent advances in DNA microarray allow us genome-wide analysis of genetic alterations including DNA copy number changes, mutations, and gene expression in cancers. We tried to establish array-based CGH with high resolutions, high quantitative capability and sensitivity, and applied this novel powerful method to mapping the putative oncogenes in cancers. Our arrayed CGH showed quantitative analysis of DNA copy number in the range from 1 to 10,000 copies. We detected 10 copies of the gene per cell. We also performed gene expression monitoring of gastric cancer using microarray with 4,000 cDNAs of known genes and identified many kinds of genes that were specifically expressed in gastric cancer. Less

(1997) 尽管临床技术有所发展，但许多癌症的预后仍然较差。比较基因组杂交 (CGH) 可用于鉴定与癌发生相关的新癌基因和抑癌基因。对 30 份新鲜冷冻胆囊癌组织进行了研究，12p 染色体增益与 III 期和 IV 期相关（P<0.05）。因此，12p 的增加可能是胆囊癌的潜在预后因素 2) 卵巢癌；为了发现耐药肿瘤的遗传变化，我们对 21 种原发性卵巢癌和一些细胞系进行了 CGH。 1p、1q 和 19p 区域以及 2p 和 15q 区域的缺失与顺铂耐药表型相关。紫杉醇耐药性在 MDR 基因所在的 7q 染色体上增加，目前的研究结果表明，这些染色体的增加和减少可能是预测卵巢癌患者耐药性的潜在指标。在基于顺铂和/或紫杉醇的化疗之前 3) 神经母细胞瘤；我们对 24 例神经母细胞瘤进行了 CGH 和双色 FISH 来鉴定遗传。与进行性神经母细胞瘤相关的畸变在所有进行性 4 期神经母细胞瘤中都发现了新的染色体增益。此外，通过使用粘粒克隆进行 FISH 分析，1q21-q25 增益缩小到 1q23。 1q23 可能在晚期进行性神经母细胞瘤的发展中发挥作用。(1998) 澄清针对退行性和进展性神经母细胞瘤的生物学特征，对 67 名神经母细胞瘤患者进行了 CGH。所有退行性肿瘤（1-3 期和 4s）的 CGH 数据显示了整个染色体部分的全染色体畸变。揭示了染色体区域部分的染色体增益和丢失，我们的数据表明神经母细胞瘤在生物学上分为两个不同的组，其中一组显示进行性疾病，另一组显示进行性疾病。有部分染色体变化，而另一种模仿晚期 3/4 神经母细胞瘤，但表现出具有整体染色体畸变的退行性疾病。(1999) DNA 微阵列的最新进展使我们能够对遗传改变进行全基因组分析，包括 DNA 拷贝数变化、突变、我们尝试建立具有高分辨率、高性能和灵敏度的基于芯片的 CGH，并应用这种定量的新颖强大方法来绘制癌症中假定的致癌基因。我们的阵列 CGH 显示了 1 至 10,000 个拷贝的 DNA 拷贝数的定量分析，我们还使用 4,000 个已知基因的 cDNA 进行了胃癌的基因表达监测。多种在胃癌中特异表达的基因较少。