Genetic alterations involved in initiation and progression of human cancer

1.在染色体异常多发区域中，12q、17p和18q三个染色体区域的缺失与胰腺癌的预后不良有关。在Smad4纯合子缺失的胰腺癌细胞系中，携带Smad4基因的非病毒载体未显示出对细胞生长的抑制作用。我们以前报道过18q缺失是胰腺癌发生的早期事件。Smad4基因突变可能是胰腺癌发生的始动步骤和预后决定因素。然而，18q上可能存在与Smad4.2不同的未知抑癌基因。我们和其他人之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尝试。体外实验成功，导入正常拷贝的PTEN可诱导肿瘤细胞发生凋亡，但体内实验未获成功。这些结果表明，PTEN基因经过适当的改良后，可以作为子宫内膜癌基因治疗的候选基因。在人类肺癌中，DMBT1基因座经常发生10q的缺失。此外，该基因还存在突变和表达抑制现象。DMBT1有可能作为肿瘤抑制基因在人肺癌发生中发挥作用。在神经母细胞瘤中，研究了14q的等位基因丢失，并确定了14q32上常见的500kb的缺失区域。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体内的1p32断裂点。我们正试图分离导致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.