高惡性度胃MALToma之分子分類法:尋求可預測幽門桿菌依賴性腫瘤之基因表現圖譜
Other Title
Molecular Classification of High-Grade Gastric MALToma: identification of
gene expression profile predicting H. pylori-dependence of the tumor
gene expression profile predicting H. pylori-dependence of the tumor
Date Issued
2003
Date
2003
Author(s)
鄭安理
DOI
913112B002009
Abstract
Mucosa-assocaited-lymphoid tissue lymphoma (MALToma) of stomach is the
most common extranodal lymphomas of humans. Gastric MALToma is classified
into high-grade (HG) and low-grade (LG) subtypes by histological criteria. LG
gastric MALToma is characterized by its closely association with Helicobacter
pylori (HP) infection; and eradication of HP by antibiotics cures 50-70% of this
tumor. However, HG gastric MALToma, in contrast to its LG counterpart, was
once believed to consist of highly-transformed cells, of which growth is independent
of HP. We were the first group of investigators who demonstrated that nearly
60% of early-stage HG gastric MALToma remains HP-dependent and can be cured
by HP eradication (J Clin Oncol 2001; 19:4245-51). Clinically, it is most
important to predict HP-independence state of freshly diagnosed HG gastric
MALToma, since the latter may progress rapidly if unresponsive to anti-HP therapy.
However, histologic or molecular features, which predict HP-dependence of this
tumor, remain elusive. We hypothesize that molecular mechanisms of
HP-dependence may be different between LG and HG gastric MALToma. For
example, genetic aberration such as t(11;18)(q21;q21), which results in chimeric
protein API2-MALT1 and is closely associated with HP-independent state of LG
gastric MALToma, dose not seem to exist in HG gastric MALToma.
This study aims to identify molecular and cellular markers, as well as gene
expression profiles, which may help predict HP-dependence state of HG gastric
MALToma. Further clarification of the biologic significance and function of novel
HP-dependence-relevant genes will be done.
In the first year of the project, we have already identified two molecular markers
and two immunologic cellular markers that are closely associated with
HP-independence state of HG gastric MALToma. We have demonstrated that
nuclear expression of BCL10 has a sensitivity of 85.7%, and a specificity of 100%
to predict HP-independence of HG gastric MALToma. In addition, confocal
immunofluorescence microscopy revealed that nuclear expression of NF-B
correlated well with the aberrant BCL-10 nuclear expression; and nuclear expression
of NF-B alone predicts HP-independence with a sensitivity of 85.7% and a
specificity of 86.4%. We confirmed that t(11;18)(q21;q21) rarely occur in HG
gastric MALToma. Therefore, BCL10 nuclear translocation appears to be a major
independent event in predicting HP-independence of HG gastric MALToma. We 4
are currently working on clarification of the mechanism and biologic significance of
BCL10 nuclear translocation in HP-independent HG gastric MALToma.
Two immunologic cellular markers were found to be relevant to
HP-independence state of HG gastric MALToma. We showed that non-expression
of CD86 of MALToma cells is a useful marker for predicting HP-independence of
HG gastric MALToma. The expression of CD86 was detected in 9 (64%) of 14
HP-dependent high-grade gastric MALTomas but in none of 6 HP -independent
cases (p=0.010). We reason that loss of co-stimulatory markers may preclude
tumor cell/reactive T-cell interaction and contribute to the transition to
HP-independent state of HG gastric MALToma. Finally, we discovered that
decreased infiltration of NK cells in tumor tissues is associated with
HP-independence of HG gastric MALToma. We found that HP -dependent HG
gastric MALToma contained significantly higher numbers of CD56 (+) NK cells than
HP -independent cases (2.7 ±1.2% versus 0.80±0.70%; p=0.005). CD56 (+) nature
killer (NK) cells are thought to suppress the growth of HP- related autoreactive and
neoplastic B lymphoid cells of the stomach. These molecular and immunologic
cellular markers will be immediately useful for the physicians to select the right
modality of treatment for patients with HG gastric MALToma.
We have thus far collected 20 freshly frozen tissue samples of HG gastric
MALToma, of which the HP-dependence state has already been verified by
prospective clinical study. Microarray approaches to identify gene expression
profiles of HP-dependent and HP-independent tumors are ongoing. Among 20
freshly frozen tissue samples of HG gastric MALToma, 16 samples containing
microdissectable HG and LG MALToma cells are identified. Comparison of the
expression profiles of the co-existing LG and HG counterparts of the same gastric
MALToma patient is ongoing. These ongoing studies will help clarify whether the
two components of MALToma may belong to two different clones, and genetic
changes responsible for HG transformation may not be the same as those responsible
for HP –independence transformation.
Subjects
High-grade gastric MALToma
HP-independence
BCL10
NF-κB
CD86
and CD56 (+)NK cells
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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