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

为了了解胰腺癌的分子特征，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的杂合性缺失（LOH）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tgf - β rii、IGFIIR、BAX和PTEN的可能改变的关系。在胰液样本中进行FISH分析以评估其对胰腺癌诊断的意义，以及tp53相关基因p73和p33/ING1的改变。结果显示：预后不良与12q、17p、18q的LOHs显著相关。MSI- h在40%的原发性胰腺癌中显示MSI，在15%的原发性胰腺癌中观察到更多的标记物，然而，候选靶基因没有改变。详细分析发现6q21、6q23-q24、6q26、12q21和12q22-q23.1等位基因频繁丢失。构建人类细菌人工染色体以覆盖缺失区域。DUSP6和TDG被鉴定为候选肿瘤抑制基因，在绝大多数分析的胰腺癌细胞系中表达降低。胰液- fish分析显示13例非肿瘤样本中拷贝数无异常，而19例肿瘤样本中有12例拷贝数异常。涉及2个或更多标记的异常与恶性表型显著相关。除一种乳腺癌组织外，P73在各种癌症组织中均未发生改变。p24/ING1- alt1和p47/INGI-ALT2被鉴定为p33/ING1的替代转录本。这些结果使我们得出结论：检测等位基因丢失对胰腺癌的诊断和预后预测具有重要意义，可能存在一条包含未知msi靶基因的发展和进展的独家途径，新的候选肿瘤抑制基因如DUSP6和TDG可能在胰腺癌的发生和进展中发挥作用。少

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