宿主易感性與宿主－微生物交互作用在胃黏膜相關淋巴瘤發生與進展的角色(2/3)
Other Title
Host susceptibility and host-microbe interaction in the development and
progression of gastric mucosa-associated lymphoid tissus lymphoma(2/3)
progression of gastric mucosa-associated lymphoid tissus lymphoma(2/3)
Date Issued
2004
Date
2004
Author(s)
林肇堂
DOI
922314B002123
Abstract
Gastric mucosa-associated lymphoid tissue lymphoma (Maltoma) have
received increasing attention in recent years because of their unique
histologic and clinical features. Stomach is the most common site of
Maltoma and represent 40~50% of gastric lymphoma with increasing
incidence. In comparson with nodal B-cell lymphoma, gastric Maltomas are
usually at low stage when diagnosed and slow to disseminate. Several lines
of evidence, including histomorphological, epidemiological,experimental and
clinical data, suggest H. pylori infection is closely linked to gastric Maltoma.
However, there remain a substantial portion (20~40%) of gastric Maltoma
unresponsive to antibiotic treatment and only a minority of H. pylori-infected
patients may develop gastric Maltomas. Which factors will determine the
success or failure after eradication of HP and why only some susceptible
patients suffered from gastric Maltoma remain unknown. Although
high-grade transformation was initially assumed unresponsive to anti-H.
pylori therapy, our study and others have recently shown the response rate
is independent of histological grading. Therefore, to distinguish responsive
and unresponsive cases and to separate the disease-causing infection from
the silent infection remains a great challenge for optimizing management of
H. pylori-related diseases and gastric Maltomas.
Enhanced gastric inflammation and risk of developing gastric Maltomas
is a consequence of an inappropriate host response to the chronic presence
of H. pylori within the gastric niche. Because gastric inflammation provides a
common denominator that translates into the different outcomes of
host-microbe interaction, genes involved in regulating antimicrobial immunity
and inflammation may modulate the risk after exposure to H. pylori. Family,
twin, animal and case-association studies provide evidence that the
intensity of inflammation and degree of gastric epithelial lesions may vary
with genetic differences in host response. On the basis of above assumption,
particular combination of multiple genes may confer susceptibility and only a
small number of individuals who encounter H. pylori infection will develop
diseases according to different genetic background of the host. Therefore,
relating genetic differences to disease phenotypes may potentially allow
more accurate prediction of variable outcomes of H. pylori and appropriate
adjustment of treatment stragegies, as well as indicating novel area for
future studies of H. pylori-associated diseases.
In the first year grant period, we have enrolled 70 patients with maltoma
and 310 healthy controls. Genomic DNAs were extracted from peripheral
white blood cells. Polymorphism analyses for IL-1 β (-31 C/T & -511 T/C), IL-6 (-174 G/C), TNF-α (-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031
T/C), TNFR1 (-383 A/C) and TNFR2 (codon 196 T/G) were performed with 4
polymerase chain reaction (PCR) followed by direct sequencing for IL-1 β
(-31, -511) and TNF-α (-238, -308, -857, -863, -1031), and PCR combined
with restriction enzyme length polymorphism for IL-6, TNFR1 and TNFR2.
Genotype frequencies showed no differences between patients with
Maltoma and controls for IL-1 β, IL-6, TNFR1, or TNFR2. For TNF α, the
TNF-α-857T variant, corresponding to low transcription activity, was
significantly underrepresented in Maltoma compared to controls (6.4% vs.
14.3%, p=0.018), conferring a 3-fold decrease in risk (odds ratio:0.33, 95%
confidence interval 0.15~0.75). Considering the low transcription activity of
TNF-α-857T variant and the central role of TNF-α in development of
lymphoma, our preliminary results are helpful for lymphomagenesis and
provide first evidence that genetic host factors play a key role in Maltoma.
Genetic polymorphisms in glutathione s-transferase (GST) and
interleukin (IL) -1 β have been reported to influence interethnic and
interindividual susceptibility to Maltoma, we tested whether polymorphic
variations in GSTM1, GSTT1, GSTP1, IL-1 β and IL-1 receptor antagonist
(IL-1RN) confer susceptibility to Maltoma in the second year grant period.
DNA samples were collected from 75 patients and 321 controls. Genotypes
were determined by PCR-based techniques. Prevalences of variant
genotypes in the control group were GSTM1 null 52.4%, GSTT1 null 43.0%,
GSTP1 105 val/val 7.4%, GSTP1 105 Ile/val 25.9%, IL-1 β –511 T/T 19%,
-511 C/T 54.2%, and IL-1RN 1/2 & 2/2 11.2%, as expected for Chinese but
somewhat different from those reported for Caucasians. The rates of
GSTM1, GSTP1, IL-1 β and IL-1RN genotypes did not differ between
patients and controls. However, GSTT1 null genotypes were significantly
more common in Maltoma patients (43/75 vs. 138/321, p=0.029; OR=1.8,
95% CI:1.1~3.0) as compared to controls. These data support the notion
that interindiviaual differences in susceptibility to H. pylori-associated
Maltoma may be mediated in part through inherited variability in the
inactivation and detoxification of carcinogens. Furthermore, our results
suggest the effects of these genotypes show interethnic variations.
In the following third year grant period, we will extend our study to
investigate chemokine gene polymorphisms in the development and
progression of Maltoma. Furthermore, the genotypes will be correlated with
treatment response. Besides, genomewide host profiling with cDNA
microarray to search for some potential novel candidate genes and
polymorphism will be performed and launched for association studies.
Subjects
Host susceptibility
cytokine polymorphism
mucosa-associated lymphoid tissue lymphoma
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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