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Gastric cancer is the second leading cause of cancer death worldwide, killing upwards of one million people each year. Apoptosis, a genetically controlled cell death in multicellular eukaryotic organisms, is an important mechanism for embryonic development, immune-system function and maintenance of tissue homeostasis through activation of an intrinsic suicide program to eliminate superfluous, infected, transformed or damaged cells. Single nucleotide polymorphism (SNP) is the most abundant type of genetic variations and is considered to be an important endogenous cause and fundamental factor influencing cancer risk. We conducted a hospital-based case-control study to investigate the association between apoptosis related genes and the risk for gastric cancer. We continuously enrolled 205 patients with pathologically proved gastric cancer and 397 frequency-matched healthy controls at Kaohsiung Veterans General Hospital from 2003 to 2006. Blood derived DNA samples from all participants were genotyped by PCR-RFLP to identify eight SNPs on seven key genes (FAS, FASL, SURVIVIN, XIAP, CASP3, CASP8, CASP9) in apoptotic pathway, but only five SNPs on four genes (FAS, FASL, CASP3, CASP9) were eventually valid for subsequent analyses. Our results showed that significant effects of H. pylori infection, cigarette smoking, alcohol drinking, and consumption of salted food and fermented food on gastric cancer risk while coffee drinking and consumption of vegetables and fruits had significant protective effects against gastric cancer in our study cohort. None of the individual gene polymorphism was associated with the risk of gastric cancer. However, the gene-gene interaction between CASP3 A21926C and CASP9 codon Arg221Gln polymorphisms was significantly associated with gastric cancer risk. In the combined analysis of four apoptosis related genes, our data showed that individuals carrying three or more putative high-risk genotypes were significantly associated with the development of gastric cancer than those who carrying two or less putative high-risk genotypes. Besides, the CASP9 codon Arg221Gln polymorphism was a risk factor for gastric cancer in people equal to or elder than fifty, though not in people younger than fifty. Taken together, our results indicated that SNPs on apoptosis related genes were associated to the development of gastric cancer.

In the past study, we used a human gastric stem cell clone, KMU-GI2, isolated from endoscopically biopsied gastric mucosa. As we maintained this KMU-GI2 cell clone, we also found a subclone with spontaneous transformation, named KMU-CSN. We found this KMU-CSN cell line showed homogenous epithelial morphology, cell pile-up appearance due to contact insensitivity, enhanced anchorage independence (from 1.7% of KMU-GI2 to 22% of KMU-CSN) and cell immortalization (CPDL >100). The high tumorigenic potential of this KMU-CS12 cell line has been endorsed by the finding of the tumor formation in nude mice. By spectral karyotyping and SNP GeneChip® Mapping 500K Assay, we found chromosomal abnormalities in chromosome 12, which were derived from duplication of 7p15.1~15.3 and 7p22.1~22.3. In normal cells, HOXA genes were found to localize in chromosome 7. In this KMU-CS12 cell line, an increased expression of HOXA4¡B5¡B7¡B9¡B13 genes was also shown, as compared with KMU-CSN. With these findings, we hypothesized that HOXA genes may play a role in gastric carcinogenesis. Therefore, we can check the prevalence of HOXA genes abnormalities in human gastric cancer patients.

Thesis--M. Phil., University of Hong Kong.