Genome 2000 基因體分析研討會

Genetic Instability in Gastric Cancer

Jeou-Yuan Chen

Institute of Biomedical Sciences, Academia Sinica

Gastric cancer (GC) is highly prevalent. In spite of a decreasing incidence, it is the second most frequent cancer in the world (after lung cancer). It also ranks as the second leading cause of cancer death worldwide, and in some countries, especially those of the Far East such as China, Japan, and Korea, it is the leading cause of cancer death. The prognosis of GC patients is dismal because the majority of them were found to have advanced disease at the time of diagnosis. Despite the overall international importance of gastric carcinoma, little effort has been made to identify useful forms of systematic management. A step in the direction of advancing the treatment of this disease would come from a better understanding of the tumor and its behavior. Genetic instability is a cardinal feature of the multi-step process of tumor formation. Mutational alterations conferring tumor instability include the subtle changes in DNA sequence as well as cytogenetically visible changes, that both provide cancer cells with a selective growth advantage and lead to the outgrowth of a tumor. To gain a better understanding of the pathogenic development of gastric cancer, we have examined different forms of genetic instability in a series of GC. Chromosomal instability that results into the increase or decrease of chromosome DNA copy numbers was monitored by comparative genomic hybridization. An array of recurrent chromosomal abnormalities were identified. Among them, chromosomal loss at 18q and gains at 17q and 20q were significantly correlated to specific features of patient- or tumor-related factors, suggesting that the chromosomal abnormalities at these regions may predominate a specific pathway of gastric tumor initiation and/or progression. A genome-wide instability at simple repeat sequences was also characterized. Microsatellite instability (MSI) was measured at 59 dinucleotide repeat loci that detected at least one site per arm of each autosome, and the tumors were divided into the high MSI (MSI-H), low MSI (MSI-L), and microsatellite stable (MSS) tumors. Statistical analysis revealed a strong correlation between tumors with MSI at multiple loci and the expanding type of growth pattern according to Ming's histological classification (P = 0.001), suggesting that advanced GC with a high frequency of MSI progresses preferentially in an expanding mode. These results further confirmed that MSI in gastrointestinal carcinomas identifies a subset of tumors with a pathologically distinct phenotype when it occurs at multiple loci, and that low MSI and MSS tumors are clinicopathologically indistinguishable. The underlying causes that lead to the various forms of genetic instability will be discussed.