胃癌致病機轉：以cytokine和chemokine基因單核甘酸多型性探討宿主敏感性角色(2/3)
Date Issued
2004
Date
2004
Author(s)
吳明賢
DOI
922314B002122
Abstract
Gastric cancer (GC) is the second most common malignancy in the world. In Taiwan, GC remains the fourth leading cause of cancer death with
more than 2000 persons dying of this devastating disease annually. The pathogenesis of GC is complex and consists of two interacting elements:
genetic susceptibility and environment factors. In the past decades, much attention has been paid to the environmental risks of GC. Considerable evidence has pointed out that H. pylori infection and smoking are among the major determinants of GC. However, only a small portion of patients exposed to environmental stimuli develop GC. Recently, new evidence has
emerged suggesting that host genetic factors also play a critical role.
Specifically, the host response to environmental triggers, rather than bacteria or environmental factors per se, may confer susceptibility to or
protection against GC.
In the multistage model of gastric carcinogenesis, gastric inflammation is a prerequisite for the development of GC. Therefore, factors involved in initiation and regulation of the inflammatory responses may play a pivotal role in determining outcomes and genetic factors, like various H. pylori strains or environmental toxins, may operate at the level of gastric inflammation. In this respect, the intrinsic role of cytokines and chemokines
as modulators of anti-microbial immunity and inflammatory responses makes them attractive candidates as a key regulator influencing the
outcome of gastritis. It was assumed that the critical balance between proand anti-inflammatory cytokines would dictate the outcomes of gastric inflammation and development of GC might be facilitated in a permissive
cytokine environment by combination of different unregulated or down regulated cytokine gene expression.
Both H. pylori infection and cigarette smoking could induce cytokine and chemokine expression in the stomach. The in vitro maximal capacity to
produce different cytokines varies among different individuals. Such inter-individual differences can be attributed to single nucleotide polymorphisms (SNPs) in the coding or promoter regions of cytokine genes.
SNPs may affect the overall expression and secretion of cytokines. Therefore, different host cytokine responses determined at the genetic
(transcription) level may explain why there is a variety of individual susceptibility to a given microbial infection or environmental toxins. These developments allow us the opportunity to investigate the role of SNPs in key immunoregulatory molecules-cytokines, chemokines, and their receptors on the relative risk of GC for a given individual. Two recent studies have indeed provided evidence that SNPs of IL-1β are associated with the risk of GC.
However, such study was performed mainly in Caucasians and the genotype status varies greatly between different ethnic backgrounds.
Furthermore, studies concerning gene-environment and gene-gene interactions remain lacking.
In the first year grant period, we analyzed 11 functional polymorphisms in tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-4 and IL-10 genes (Table 1) in 220 Taiwanese Chinese with GC and in 230 healthy controls. The risk of genotype was adjusted with confounding environmental risks. Our results revealed that the frequency of Helicobacter pylori infection
[odds ratio (OR) 1.7, 95% confidence interval (CI) 1.19~2.56], cigarette smoking (OR:2.02, 95%CI 1.38~2.95) and high IL-10 producer genotype
(OR:2.67, 95%CI 1.29-5.50) was significantly increased in the entire GC patients. Among different subtypes of GC, a higher risk of developing diffuse type (OR:1.64, 95%CI 1.01~2.67) or cardia cancer (OR:2.44, 95%CI
1.13~2.67) was observed for the CT/CC genotype of IL-4 at the position –590, whereas the high IL-10 producer genotype was significantly linked with the risk of cardia cancer (OR:3.21, 95%CI 1.06-9.73) or advanced stage (OR:2.29, 95%CI 1.12-4.64). No association was noted between GC and controls in the distribution of IL-1 and TNF-α genotypes.
Logistic regression analyses revealed that H. pylori infection (OR:1.7, 95%CI 1.14~2.52), cigarette smoking (OR:1.87, 95%CI 1.27-2.96) and IL-10 genotype (OR:2.54, 95%CI 1.24~5.61) are independent risks for GC.
Independent efects of IL-10 genotype, H. pylori infection and cigarette smoking indicate that carcinogenesis of GC is influenced by a variety of host and environmental factors.
In the second year grant period, analyses of gene expression in AGS induced by different strains of H. pylori has been performed by cDNA
microarray. We have found some differences among bacterial strains from various disease (ulcer vs. cancer vs. maltoma). In addition, case and control enrollment keeps continuing and is more than 250 in numbers. Genetic
polymorphisms in TNF-α (-238, -308, -857, -863, -1031), TNFR1 (-383), TNFR2 (cadon 196), CD14 (-159), TLR4 (Asp299 Gly and Thr 399 Ile) and
IL-8 (-251) have been investigated in GC, maltoma and controls. Our results demonstrated TNF-α –857 C→T was significantly underrepresented in maltoma compared to controls (6.4% vs. 14.3%, p=0.018), conferring a 3-fold decreased in risk (OR=0.33, 95%CI 0.15-0.75). Comparison of allele frequencies between GC and controls failed to show any statistical
significance. The differences in genetic background as well as divergent clinicopathologic features between GC and multoma supports the notion that fundamental mechanistic differences exist in these 2 well-defined H. pylori-associated maliguancies.
In the third year grant period, we will collect at least 300 cases of GC with different but well-characterized phenotypes for further genotypic
analyses. The novel genes with biologic significance in H. pylori-associated diseases disclosed by cDNA microarray will be tested for their roles in host susceptibility of gastric carcinogenesis.
Subjects
Gastric cancer
Helicobacter pylori
Genotype
Host Susceptibility
SDGs
Publisher
臺北市：國立臺灣大學醫學院一般醫學科
Type
journal article
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