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Genomic analysis of human gastrointestinal tumors 1. During the past several years, we have systematically analyzed the global gene expression profiles in liver and gastric cancers. We identified many genes that are differentially expressed in tumor and non-tumor tissues, as well as genes that are associated with phenotypic and genotypic variations of tumors. We are continuing these projects and expanding to wider variety of tumor samples. We are also analyzing the molecular function of some of the genes identified from the study. One such example is PLA2G2A, the gene encoding the group IIa secreted phospholipase A2. We found that patients whose gastric tumor had high expression levels of PLA2G2A had a highly significant survival advantage. The murine ortholog of PLA2G2A, Mom1, has been shown genetically to limit the severity of intestinal neoplasia in the Apcmin1/+ mouse, a mouse model of colon cancer. We are studying the function of PLA2G2A in gastric cancer progression using cell biological, biochemical, genetic and genomic methods. 2. Tumor development is a multistage process. Gastric cancer generally begins as intestinal metaplasia and dysplasia. We are studying the gene expression programs involved in these pre-malignant lesions and compare them with normal gastric mucosa and invasive tumor tissues. We are particularly interested in identifying transcription factors that are important in the pre-malignant transformation. The study will provide new insight into the molecular basis of tumorigenesis. 3. The amplification of oncogenes and deletion of tumor suppressor genes, the result of genetic instability, play a critical role in the development of cancer. We are using array based comparative genomic hybridization (aCGH) to map chromosomal abnormalities in gastrointestinal tumors. These aCGH analyses will lead to the identification of regions of recurrent gene amplification and deletion in these tumors. Correlation aCGH with gene expression profiles will allow us to identify candidate oncogenes and tumor suppressor genes. 4. Tumor resistance to chemotherapeutic agents is one of the major obstacles in the clinical management of human cancers. We are applying genomic analysis to study drug resistance. We are particularly interested in two chemotherapeutic agents: 5-FU in gastric cancer and gemcitabine in pancreatic cancer. Genomic techniques will be applied in both tumors samples and cellular models of intrinsic and acquired resistance to drugs. The identification of specific gene expression patterns associated with drug resistance will also support the use of gene expression profiling to predict response in cancer patients prior to treatment. The long term goal of the study is to understand the molecular basis of drug resistance, help design novel therapeutic regimens, and ultimately circumvent resistance to chemotherapy. Chen X, Cheng ST, So SK, Fang ST, Barry C, Higgins J, Lai K, Ji J, Dudoit S, Ng I, vandeRijn M, Botstein D and Brown PO: Cheung ST, Chen X, Guan XY, Wong SY, Tai LS, Ng IO, So SK and Fan ST: Ji J*, Chen X*, Leung SY*, Chi J, Chu KM, Yuen SY, Li R, Chan A, Li J, Dunphy N and So S: (*co-first authors) Xu RH, Chen X, Chen DL, Li R, Addicks GC and Thomson JA: Leung SY*,Chen X*, Chu KM, Yuen SY, Mathy J, Ji J, Chan A, Li R, Law S, Troyanskaya OG, Tu IP, Wong J, So S, Botstein D and Brown PO: (*co-first authors) |
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Copyright © 2005 The Regents of the University of California. Last updated: September 22, 2005 |