Epigenetics and Genetics of Stromal Cells in Liver and Gastric Cancer

Columbia University Health Sciences, New York NY

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Abstract

Genetic and epigenetic aberrations are well studied hallmarks of cancer cells. But in addition, an increasing[unreadable] number of reports have suggested that such changes can also occur in the non-neoplastic stromal cells that[unreadable] surround and intermingle with carcinoma cells. There are also recent functional data suggesting that tumorassociated[unreadable] stromal cells, including myofibroblasts and tumor-associated endothelial cells (TECs), can[unreadable] acquire new phenotypes, different from normal stromal cells, which actively contribute to tumor progression.[unreadable] An obvious challenge is to link these two lines of research, pinpointing the specific genetic and epigenetic[unreadable] changes that might account for the new phenotypic characteristics acquired by tumor-associated stromal[unreadable] cells.[unreadable] In this Project we will carry out a genome-wide analysis of chromosomal and sub-chromosomal aneuploidies[unreadable] (DNA copy number aberrations; CNA), loss of heterozygosity (LOH) and gains and losses of DNA[unreadable] methylation (GOM, LOM) in the myofibroblasts that proliferate in human cirrhotic livers and hepatocellular[unreadable] carcinomas, and in stromal myofibroblasts from gastric cancers. To achieve this objective, we will apply a[unreadable] new method, methylation-sensitive SNP chip analysis (MSNP), that we have recently tested and validated[unreadable] for combined genetic and epigenetic profiling in other types of human cancers and normal tissues. First, we[unreadable] will use MSNP to obtain comprehensive genetic (CNA, LOH) and epigenetic (GOM, LOM) profiles of[unreadable] myofibroblasts from normal human livers, cirrhotic human livers and human hepatocellular carcinomas.[unreadable] Second, we will carry out parallel experiments analyzing stromal myofibroblasts from human gastric cancers,[unreadable] comparing the epigenetic and genetic profiles of these cells to control myofibroblasts from normal human[unreadable] stomach. Third, we will validate the MSNP data for loci that show recurrent genetic or epigenetic changes,[unreadable] using independent molecular methods.[unreadable] We expect that the genetic and epigenetic data from this Project will allow the other Projects to formulate[unreadable] and test new biological hypotheses for the role of stromal cells in human liver and gastric cancers, as well as[unreadable] in pre-neoplastic liver cirrhosis.