Genetic alterations involved in initiation and progression of human cancer

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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.