Establishment of efficient treatment strategies for the pancreatic cancer based on its molecular characteristics

基于胰腺癌分子特征建立有效治疗策略

• 批准号: 10557116
• 负责人: FURUKAWA Toru
• 金额: $ 8.51万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557116/
• 关键词: pancreatic cancer; genetics; loss of heterozygosity; prognosis; FISH; tumor suppressor gene; microsatellite instability; DUSP6; 悪性腫瘍; LOH; TP53; p73; p33; ING1; 膵癌; 発癌メカニズム; 遺伝子診療; 遺伝子異常; DNAミスマッチ修復; 治療抵抗性

To know molecular characteristics of the pancreatic cancer for establishment of novel diagnostic procedure and efficient therapy to make prognosis better, we investigated loss of heterozygosity (LOH) of autosomes in the pancreatic cancer specimens and their relationships with clinicopathological features of the patients, microsatellite instability (MSI) and possible alterations of its candidate target genes including TGFβRII, IGFIIR, BAX, and PTEN, putative tumor suppressor gene-loci on 6q and 12q, FISH analysis in the pancreatic juice samples to evaluate its implication for diagnosis of the pancreatic cancer, and alterations of TP53-related genes, p73 and p33/ING1. Results were shown as follows : A poor prognosis was significantly associated with LOHs of 12q, 17p, and 18q. MSI-H showing MSI in 40% and more markers was observed in 15% of primary pancreatic cancers, however, none of the candidate target genes altered. Detailed analysis revealed frequent allelic losses at 6q21, 6q23-q24, … More 6q26, 12q21 and 12q22-q23.1. Human bacterial artificial chromosomes were constructed in contig to cover the deleted regions. DUSP6 and TDG were identified as candidate tumor suppressor genes whose expressions were reduced in vast majority of pancreatic cancer cell lines analyzed. The pancreatic juice-FISH-analysis revealed none of copy number-abnormalities in 13 non neoplastic samples while the abnormalities in 12 out of 19 neoplastic samples. The abnormality involving 2 or more markers was significantly associated with malignant phenotype. p73 was not altered in various cancer tissues except in one breast cancer tissue. p24/ING1-ALT1 and p47/INGI-ALT2 were identified as alternative transcripts of p33/ING1. These results led us to conclude that detecting allelic loss is quite useful for diagnosis and predicting prognosis, an exclusive pathway for development and progression involving unidentified MSI-target genes possibly exist, novel candidate tumor suppressor genes like DUSP6 and TDG may play a role in pancreatic carcinogenesis and progression. Less

为了解胰腺癌的分子生物学特征，建立新的诊断方法和有效的治疗方法，改善预后，我们研究了胰腺癌标本中常染色体杂合性缺失（洛）及其与患者临床病理特征、微卫星不稳定性（MSI）及其候选靶基因TGFβRII、IGFIIR、BAX和PTEN的可能改变的关系，在6 q和12 q上的假定肿瘤抑制基因位点，在胰液样品中进行FISH分析以评估其对胰腺癌诊断的意义，以及TP 53相关基因、p73和p33/ING 1的改变。结果表明：12 q、17 p和18 q的LOH与预后不良显著相关。MSI-H显示MSI在40%和更多的标记物中在15%的原发性胰腺癌中观察到，然而，没有候选靶基因改变。详细的分析显示，在6 q21，6 q23-q24， ...更多信息 6 q26、12 q21和12 q22-q23.1。以重叠群构建人细菌人工染色体以覆盖缺失区域。DUSP 6和TDG被鉴定为候选肿瘤抑制基因，其在所分析的绝大多数胰腺癌细胞系中表达降低。13例非肿瘤性胰腺癌组织中无拷贝数异常，19例肿瘤性胰腺癌组织中有12例拷贝数异常。2个或2个以上标志物的异常与恶性表型显著相关。除一个乳腺癌组织外，p73在各种癌组织中均未改变。p24/ING 1-ALT 1和p47/INGI-ALT 2被鉴定为p33/ING 1的替代转录物。这些结果提示检测等位基因丢失对胰腺癌的诊断和预后判断非常有用，MSI靶基因可能是胰腺癌发生发展的唯一途径，新的候选抑癌基因如DUSP 6和TDG可能在胰腺癌的发生发展中起作用。少

项目成果

Carsinoma of the pancreas and biliary tract-recent underlying problems

胰腺和胆道癌——近期潜在问题

• 发表时间: 1998
• 作者: Furukawa;T.;et al.
• 通讯作者: et al.

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