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

(1997)尽管临床技术的发展，许多癌症的预后仍然很差。比较基因组杂交(CGH)有助于发现与肿瘤发生有关的新的癌基因和抑癌基因。1)胆道癌：对30例胆囊癌新鲜冰冻组织行CGH。12P的染色体增加与III期和IV期相关(P&lt；0.05)。因此，12P的增加可能是胆囊癌的一个潜在预后因素。2)卵巢癌：为了发现耐药肿瘤的基因变化，我们对21例卵巢癌和部分卵巢癌细胞系进行了CGH。我们发现染色体1p、1q和19p区域的增加和2p和15q区域的丢失与顺铂耐药表型有关。获得紫杉醇抗性的细胞系的mdr基因所在的染色体获得率为7q。Southern印迹分析证实mdr基因已扩增。目前的发现表明，这些染色质…在以顺铂和/或紫杉醇为基础的化疗前，更多的Somal得失可能是预测卵巢癌患者耐药性的潜在指标。3)神经母细胞瘤：我们对24例神经母细胞瘤和双色FISH进行了CGH，以确定与进行性神经母细胞瘤相关的遗传异常。在所有进展期4神经母细胞瘤中都发现了1q21-q25的新的染色体获得。此外，通过粘粒克隆的FISH分析，1q21-q25的增益被缩小到1q23。这些结果提示，1q23的DNA扩增可能在进展期神经母细胞瘤的发生发展中起作用。(1998)为了明确退行性和进展性神经母细胞瘤的生物学特性，我们对67例神经母细胞瘤患者进行了CGH检查。所有退化性肿瘤(1-3期和4s期)的CGH数据均显示整个染色体部分异常。另一方面，进展期肿瘤在染色体的区域部分有染色体的增减。我们的数据表明，神经母细胞瘤被分为两个生物学上不同的组，一组表现为进展性疾病，表现为具有部分染色体变化的进展性疾病，另一组模仿晚期3/4期神经母细胞瘤，但表现为退行性疾病，具有全部染色体异常。(1999)DNA微阵列的最新进展使我们能够对包括DNA拷贝数变化、突变和癌症基因表达在内的遗传变化进行全基因组分析。我们试图建立基于阵列的高分辨率、高定量能力和高灵敏度的计算全息图，并将这一新的强有力的方法应用于癌症中可能的癌基因的定位。我们的阵列CGH对DNA拷贝数进行了定量分析，拷贝数在1到10,000个拷贝之间。我们检测到每个细胞有10个拷贝的基因。我们还利用4000个已知基因的基因芯片对胃癌的基因表达进行了监测，并鉴定了多种在胃癌中特异表达的基因。较少

(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