Tumorigenesis, tumor suppressors, and proto-oncogenes in Down syndrome

Down syndrome (DS) is caused by trisomy 21. The risk of solid tumors among those with DS has been studied for 50 years. While many effects of trisomy are deleterious to the individual, recent epidemiological evidence suggests that people with Down syndrome (DS) have a reduced incidence of solid tumors. However, the conclusions of these studies are limited. To directly test whether DS results in a decreased incidence of solid tumors, we analyzed ApcMin-mediated tumors in DS mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Ts65Dn ApcMin mice had a 48% reduction in tumor number compared to their euploid Apc Min littermates, and a corresponding reduction in tumor size. The Ts1Rhr ApcMin mice had a 26% reduction in tumor number compared to euploid, while monosomic Ms1Rhr mice had a 101% increase in tumor number. This decreased tumorigenesis in trisomic mice corresponded with increased apoptosis in intestinal crypts. Thus, trisomy for genes on Hsa21 is protective against tumorigenesis in the small intestine, and a small subset of these genes is sufficient to provide significant protection in a dosage sensitive manner.; DS results in numerous other phenotypes, including immunological and thymic abnormalities. Transgenic mice that promiscuously over-express Ets2 have been shown to result in dramatic thymic defects, including reduced thymic size, reduced thymocyte cell number, increased apoptosis, and defects in thymocyte development. To determine whether trisomy of Ets2, in the context of DS, results in thymic abnormalities, we examined thymic morphology in Ts65Dn and Ts1Rhr mice. We determined that Ts65Dn mice have a significant decrease in thymocyte cell number, but have no alterations in gross morphology, rates of apoptosis, or thymocyte development. Furthermore, Ts1Rhr mice have no detectable thymic abnormalities, indicating that trisomy for Ets2 is not sufficient to cause thymic defects.; We also extended our analysis of tumorigenesis to cell-based assays. We demonstrated that the tumor suppressor gene TSLC1 represses tumorigenic properties of A549 cells, via a delay in cell cycle progression from G1 to S phase. We further showed that while expression of several common regulators of this G1 to S phase transition were not changed, expression levels of numerous genes were altered, including genes involved in Ras-induced senescence. We examined expression of several of these key genes in human tumors and normal lung tissue, and found similar changes in expression, validating the physiological relevance of the A549 and 12.2 cell lines.; Collectively, this work extends our understanding of tumorigenesis in DS by establishing a genetic link between trisomy and reduced solid tumor development. Our analysis of how both Ets2 and TSLC1 alter tumorigenesis and development in DS will help to clarify the etiology of this suppression of tumorigenesis.