Genetic alterations involved in initiation and progression of human pancreatic cancer

1.我们之前在人类胰腺癌染色体臂1p、6q、9p、12q、17p和18q中发现了经常缺失的区域。在这些区域中，12q、17p和18q的缺失被发现与人类胰腺癌的不良预后相关。17p和18q分别是TP53和SMAD4的基因座。在6q和12q上，分别鉴定出三个和两个最小的重叠区域（sro）。构建了6q上1个区域和12q上2个区域的BAC序列，并对这些区域的部分基因进行了分析。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表达缺失或抑制，提示这些基因的表达抑制参与了人类胰腺癌的发生。在SMAD4纯合子缺失的胰腺癌细胞系中，腺病毒介导的SMAD4基因传递没有显示出对细胞生长的任何抑制。我们认为SMAD4基因的失活与细胞生长的加速无关，而与胰腺癌发生的其他机制有关。我们报道18q的缺失是胰腺癌发生的早期事件。SMAD4基因的突变可能是胰腺癌发生的初始阶段，也是决定预后的因素。然而，18q上可能存在不同于SMAD4的未知肿瘤抑制基因。

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.