行政院國家科學委員會專題研究計畫成果報告
胃癌BAT-26標記變化的臨床病理意義與核酸誤配修復基因表現
的關係
計畫類別：■個別型計畫 □整合型計畫 計畫編號： NSC88-2314-B002-149 執行期間： 87年 8月 1日至 88年 7月 31日 個別型計畫：計畫主持人：吳明賢醫師 整合型計畫：總計畫主持人： 子計畫主持人： 註：整合型計畫總報告與子計畫成果報告請分開編印各成一冊，彙整一起繳送國科會 處理方式： □可立即對外提供參考 ■一年後可對外提供參考 □兩年後可對外提供參考 (必要時，本會得展延發表時限) 執行單位：台大醫學院內科 中華民國八十八年七月三十日1
中 文 摘 要
具有微衛星體不穩性的腸胃腫瘤是一種有較高突變率的表現型，以往用一個以上的微衛 星標記變化加上某些特定基因的突變來決定此種突變表現型的方法耗時且繁雜。最近發現位 於 hMSH2 基因 intron 5 上的一段 26 個 deoxyadenosine 標記(簡稱 BAT-26)用於大腸癌的突變 表現型決定有很好的敏感性及特異性，是單一可靠的標記。為了探討 BAT-26 的變化是否能 作為胃癌突變表現型的標記及具此種變化的腫瘤是否有特殊的臨床病理特徵，吾人收集 119 位胃癌患者的手術檢體，以聚合酵素鏈反應配合電泳分析腫瘤部和非腫瘤部 DNA 在 9 個 dinucleotide 微衛星標記，BAT-26 和 TGF-βRII 基因的變化，結果發現具有 BAT-26 變化的胃 癌和 TGF-βRII 的突變及 3 個以上的微衛星標記不穩定性密切相關，並且這些腫瘤表現特殊 的臨床病理特徵，包括位於竇部、腸道型組織型態、進行性胃癌居多、較高的幽門螺旋桿菌 感染率、較好的術後存活和較少的淋巴結轉移。這些結果顯示測試 BAT-26 的變化作為一種 篩選具特殊亞型、突變表現型及較好預後胃癌的方便且快速方法。
Table 1. Correlation of
BAT-26 alterations with replication error (RER) status
in 119 patients with gastric cancer
BAT-26 alterations
Positive (%)
Negative (%)
Total
RER-negative
0 (0)
87 (100)
87
RER-positive*
17 (53.1)
15 (46.9)
32
at 1 locus
0 (0)
5 (100)
5
at 2 loci
1 (11.1)
8 (88.9)
9
at >= 3 loci
16 (88.9)
2 (11.1)
18
* at least one of the nine locus was positive
3
Table 2. The relation of
BAT-26 alterations and clinicopathologic
characteristics in 119 patients with gastric cancer
BAT-26 alterations
Clinicopathologic
Positive
Negative
characteristics
(N=17)
(N=102)
Sex (male/female)
10/7
53/49
Age (mean±S.D. in years)
62.5±16.6
59.4±14.2
Tumor diameter (cm)
5.1±2.8
5.3±2.5
Tumor Stage
Early
1
20
Advanced
16
82
Tumor location
Antrum
13**
62
Body and Cardia
4
40
Histologic subtype
Intestinal
13*
44
Diffuse
4
58
Lymph node metastasis
Positive
6**
80
Negative
11
22
H. pylori infection
Positive
16*
64
Negative
1
38
TGF-βRII mutations
Positive
15**
0
Negative
2
102
* p<0.05 and **p<0.01 vs. negative
BAT-26 alterations
Table 3 Proportionate hazards modeling for survival in 119 patients with
gastric cancer
Variables
p value
Gender
0.6411
Age
0.0693
Tumor size
0.8699
Histologic subtype
0.3766
T classification
0.0001
N classification
0.0147
M classification
0.0005
BAT-26 alteration
0.0001
5
Fig. 1. Representative examples of
BAT-26 alterations in gastric cancer.
Abnormal bands are denoted in lanes 2, 4, 8, 10 with asterisk marks.
Fig. 2 Kaplan-Meier survival curves of 119 gastric cancer patients stratified
by positive (dash line) or negative (solid line) alterations of
BAT-26.
Abstr act
Gastrointestinal tumors with microsatellite instability (MSI) represent a mutator phenotype. It is time-consuming and laborious to determine such a phenotype by the presence of more than one microsatellite alteration together with mutations in some cancer genes that are targets of MSI. BAT-26, a repeat of 26 deoxyadenosine localized in intron 5 of hMSH2 gene, has been reported as a reliable indicator of mutator phenotype in colorectal cancers. To investigate whether BAT-26 is a useful marker for a mutator phenotype with distinct clinicopathologic features in gastric cancer (GC), 119 GC specimens and matched non-tumor tissue were examined by polymerase chain reactions with electrophoresis for 9 dinucleotide microsatellites and BAT-26, and frameshift mutations of transforming growth factor-beta type II receptor (TGF-βRII) gene. GC with BAT-26 alterations was highly correlated with multiple microsatellite alterations (>= 3 loci) and frameshift mutations of TGF-βRII, and predominantly showed antral location, intestinal histologic subtype, advanced stage, a higher rate of Helicobacter pylori infection, a better postoperative survival and less lymph node metastasis. These results show testing of BAT-26 alterations is a convenient and rapid screening method for identifying a subset of GC with a mutator phenotype and better prognosis.
7
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即將發表之論文
1. Wu MS, Lee CW, Sheu JC, Shun CT, Wang HP, Hong RL, Lee WJ, Lin JT. Alterations of BAT-26 identify a subset of gastric cancer with distinct clinicopathologic features and better
