Genetic alterations involved in initiation and progression of human pancreatic cancer

1.我们以前在人胰腺癌染色体1p、6q、9p、12q、17p和18q上发现了常见的缺失区域。在这些区域中，发现12q、17p和18q的丢失与人类胰腺癌的预后不良相关。17p和18q分别是TP53和SMAD 4的基因座。2.在6q和12q上分别鉴定出3个和2个最小重叠区（SROs）。构建6q上一个区域和12q上两个区域的BAC重叠群，并对这些区域的部分基因进行分析。3.对12q21上的DUSP6和12q24上的TDG进行分析。虽然没有发现基因组改变，但在胰腺癌细胞系中观察到这些基因的缺失或表达抑制，表明这些基因的表达抑制参与了人胰腺癌的发生。4.腺病毒介导的SMAD 4基因在SMAD 4纯合缺失的胰腺癌细胞系中的递送没有显示任何细胞生长抑制。我们认为SMAD 4基因的失活与胰腺癌发生的细胞生长加速无关，但与胰腺癌发生的其他机制有关。5.我们报道了18 q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18 q上存在与SMAD4不同的未知肿瘤抑制基因的可能性。

1.We previously identified frequently deleted region in human pancreatic cancer in chromosome arms 1p, 6q, 9p, 12q, 17p, and 18q. Among these regions, losses of 12q, 17p, and 18q were found to associated with poor prognosis in human pancreatic cancer. 17p and 18q are the loci for TP53 and SMAD4, respectively.2.On 6q and 12q, three and two smallest regions of overlap (SROs), respectively, were identified. BAC contigs for one region on 6q and two regions on 12q were constructed, and some genes in these regions were analyzed.3.DUSP6 on 12q21 and TDG on 12q24 were analyzed. Although no genomic alterations were found, loss or suppressed expression in pancreatic cancer cell lines were observed, suggesting the involvement of suppressed expression of these genes in human pancreatic carcinogenesis.4.Adenoviral 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 think that inactivation of the SMAD4 gene is not associated with acceleration of cell growth but associated with some other mechanisms in pancreatic carcinogenesis.5.We 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.