Genetic alterations involved in initiation and progression of human cancer

1.在常见的染色体畸变区域中，12 q、17 p和18 q三个染色体区域的丢失与人类胰腺癌的不良预后相关。腺病毒介导的SMAD4基因在具有SMAD4纯合缺失的胰腺癌细胞系中的递送没有显示出任何细胞生长抑制。我们以前报道过18q缺失是胰腺癌发生的早期事件。SMAD 4基因突变可能是胰腺癌发生的起始步骤，也可能是决定预后的因素。然而，在18q上存在与SMAD4.2不同的未知肿瘤抑制基因的可能性。我们和其他人先前报道了子宫内膜癌中PTEN基因的频繁体细胞突变。我们尝试通过腺病毒介导将该基因导入具有该基因两次突变的子宫内膜癌细胞系中进行基因治疗的试验。体外实验成功，导入正常拷贝的PTEN可诱导肿瘤细胞凋亡，但体内实验失败。这些结果表明，PTEN基因经过适当的改良后，是一个很好的人子宫内膜癌基因治疗的候选基因.在人肺癌中，DMBT1基因10 q的缺失是常见的，而且该基因存在突变和表达抑制。DMBT1在人肺癌的发生发展中有可能是抑癌基因.在神经母细胞瘤中，研究了14q的等位基因丢失，并确定了14q32上500 kb的共同缺失区域。还构建了含有缺失区域的BAC重叠群。另一方面，还克隆了一个发生在神经母细胞瘤患者中的1p32断裂点。我们试图分离出神经母细胞瘤的基因。

1. Among regions of frequent chromosomal aberrations, loss of three chromosomal regions, 12q, 17p, and 18q, associated with poor prognosis in human pancreatic cancer. Ade noviral mediated delivery of the SMAD4 gene in pancreatic cancer cell lines with homozygous deletion of SMAD4 did not show any suppression of cell growth. We previously reported that loss of 18q is an early event in pancreatic carcinogenesis. There is a possibility that mutation of the SMAD4 gene is responsible for the initial step of pancreatic carcinogenesis as well as prognosis defining factor. However there is a possibility of unknown tumor suppressor gene on 18q that is distinct from SMAD4.2. We and others previously reported frequent somatic mutation of the PTEN gene in endometrial cancer. We attempted a trial of gene therapy by adenovirus mediated introduction of this gene in endometrial cancer cell lines with two-hit mutation of this gene. The trial was successful in vitro, and apoptosis was induced in tumor cells after introduction of normat copy of PTEN.However, the attempt was not successful in vivo. These results suggested that the PTEN gene is a good candidate for gene therapy in human endometrial cancer after appropriate improvement.3. In human lung cancer, frequent loss of 10q at the DMBT1 locus was found. Moreover, mutation as well as suppression of expression was found in this gene. There is a possibility that DMBT1 acts as the tumor suppressor gene in human lung carcinogenesis.4. In neuroblastoma, allelic loss was studied in 14q and identified a 500-kb region of common deletion on 14q32. A BAC contig harboring the deleted region was also constructed. On the other hand, a break point on 1p32 that occurred in a neuroblastoma patient with constitutional reciprocal translocation was also cloned. We are attempting to isolate the genes responsible for neuroblastoma.