Genetic alterations involved in initiation and progression of human pancreatic cancer

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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.