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系統識別號 U0026-2708201512503400
論文名稱(中文) 宿主病理特徵及遺傳因子與易罹胃癌癌前病變相關性於胃癌病患家族之分析
論文名稱(英文) Analysis of host pathologic features and genetic factors predisposing to advanced pre-cancerous changes after Helicobacter pylori infection in gastric cancer families
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 蔡郁清
研究生(英文) Yu-Ching Tsai
學號 S98981157
學位類別 博士
語文別 英文
論文頁數 117頁
口試委員 指導教授-許博翔
指導教授-呂政展
口試委員-吳明賢
口試委員-楊曉白
口試委員-楊燿榮
口試委員-鄭修琦
中文關鍵字 胃癌  癌前病變  胃癌家屬  幽門桿菌感染  腸黏膜化生  解痙多肽化生  胃體發炎指數  基因多型性  幽門桿菌的除菌治療 
英文關鍵字 1st-degree relatives  corpus-predominant gastritis (CGI)  COX-2  diffuse type gastric cancer  familial clustering  gastric cancer  gastric cancer relatives  H. pylori  H. pylori eradication  IL-10  integrin α5β1  intestinal type gastric cancer  MMP-9  operative link on gastritis assessment (OLGA)  operative link on gastric intestinal metaplasia assessment (OLGIM)  precancerous lesions  single nucleotide polymorphisms (SNP)  spasmolytic polypeptide-expressing metaplasia (SPEM)  trefoil factor 2 
學科別分類
中文摘要 研究背景:為了預防胃癌產生,在胃癌前病變發生前治療幽門桿菌感染是很重要的。胃癌的發生常有家族群聚性,而胃癌家屬在幽門桿菌感染後常有較嚴重的胃體部發炎或胃癌前病變如腸黏膜化生(intestinal metaplasia, IM)及解痙多肽化生(spasmolytic polypeptide-expressing metaplasia, SPEM)。本研究的目的在藉由研究高風險的胃癌家屬確認我們定義的胃體發炎指數(corpus-predominant gastritis index, CGI),以及胃癌病患的子女存在的特定基因多型性是否和胃癌發生過程相關,以作為幽門桿菌感染後發生胃癌的早期高風險指標而能及早施予幽門桿菌的除菌治療。

研究方法:我們總共邀集了193位非賁門胃癌的病患和他們的389位家屬,以及173位低胃癌風險的十二指腸潰瘍病患作為對照組。參加者接受了幽門桿菌吹氣測試並提供血液檢體,萃取DNA作基因多型性測定。幽門桿菌感染陽性的胃癌病患家屬則受邀接受胃鏡檢查並在胃不同部位做病體切片,以updated Sydney’s system測定胃癌家屬及對照組胃部的發炎、胃部組織表現IM及SPEM的狀況,我們也測定了臨床上常用來分期慢性胃炎胃癌風險的operative link on gastritis assessment (OLGA) 和 operative link on gastric intestinal metaplasia assessment (OLGIM)分級系統,及我們自行研發的CGI,另外利用免疫染色法染Trefoil factor 2 (TFF2)來定義SPEM的分級,同樣用免疫染色法來分析α5β1 integrin在胃組織上皮上的表現。另外在胃癌病患家屬中分析是否有特定基因多型性明顯比低胃癌風險的十二指腸潰瘍病患比率較高,而這些基因多型性是否聯結上胃癌病患家屬胃部癌前病變的產生。

結果:胃癌病患及其一等親比起十二指腸潰瘍病患,可增加3到3.4倍產生CGI (p< 0.05)。而在胃癌病患的一等親中,有CGI者比沒有CGI者會增加5.5倍產生SPEM及5.7倍advanced SPEM的風險(p< 0.05)。而CGI也和胃體部有較高的幽門桿菌密度,產生integrin α5β1由胃上皮細胞接近基底膜的底部往上方移動,這被視為是一種integrin α5β1胃上皮細胞失去極性的表現。另外分析l95位胃癌病患的子女相較於143位十二指腸潰瘍病患有較多的機會為TGA5-1160T/ITGB1-1949A/ITGB1+31804C和COX-2-1195G/IL-10-592AA (p< 1x10-4)。這一組基因多型性在胃癌病患的子女之中增加5.3倍表現SPEM的機會(p= 0.016)。若再加上RUNX3+492A或TFF2-308CC,則在胃癌病患的子女之中增加SPEM的風險可高達112倍(p= 1x10-4)。此外,驗證胃癌患者本人胃部組織的CGI表現,發現具有CGI的比例,隨著胃部非腫瘤組織癌前病變表現分群為無癌前病變(100%)及只有SPEM者(100%)及IM、SPEM兩者皆有(82%)和只有IM者(41%)漸次下降(p< 0.05)。胃癌患者本人胃部組織具有高CGI表現的無癌前病變(100%)及只有SPEM者,平均較年輕、女生較多,腫瘤位置在胃體部較多且較晚期分化差(p< 0.05)。胃癌患者胃部非腫瘤部位及腫瘤部位組織癌前病變IM及SPEM表現具有高度相關性 (p< 0.001)。胃癌病患的子女之中表現和CGI相關的胃體部胃上皮細胞integrin α5β1上移者則比沒有者增加8.8倍advanced SPEM的風險及增加29倍基因多型性ITGB1-685-/C/ITGB1-1660AATTT/AATTT/ITGB1+32492G的機會 (p= 0.007)。另外分析CGI比例較低的胃癌患者次族群:即胃部非腫瘤部位只有表現IM的胃癌患者,發現他們比起十二指腸潰瘍病患增加4.4到5.9倍的機會合併基因多型性ITGA5-1160GG/TFF2+4649GG以及COX-2+8473TT或MMP-9-1562CC (p< 0.05)。

結論:CGI 可作為幽門桿菌感染者高胃癌風險的早期指標,而基因多型性為
ITGA5-1160T/ITGB1-1949A/ITGB1+31804C 及COX-2-1195G/IL-10-592AA,或合併RUNX3+492A 或TFF2-308C,會增加SPEM 的特異性,可作為篩檢高胃癌風險族群,以提供早期幽門桿菌治療的宿主因子指標。對於早期未表現CGI 但將來可能得癌症的族群,可考慮合併基因多型性為ITGA5-1160GG/TFF2+4649GG 以及COX-2+8473TT或MMP-9-1562CC 作為輔助的篩檢指標,值得將來在大規模研究中進一步驗證。
英文摘要 Background: To eradicate H. pylori before the occurrence of pre-cancerous changes is important to prevent gastric cancer (GCA). GCA exhibits familial clustering, and GCA families tend to present with corpus-predominant gastritis and precancerous lesions as spasmolytic polypeptide-expressing metaplasia (SPEM) or intestinal metaplasia (IM) after H. pylori infection. This study aimed to validate whether corpus-predominant gastritis index (CGI) and host genomic single nucleotide polymorphisms (SNPs) predisposed to gastric carcinogenesis processes in children of GCA patients (GCF) could offer early markers to screen high GCA risk subjects for early H. pylori eradication.

Methods: Totally 389 family relatives of 193 non-cardiac GCA patients and 173 duodenal ulcer (DU) patients as control were included initially. Blood samples for DNA extraction were collected to identify SNPs. The participants with positive urea breath test (UBT) were invited to receive panendoscope. Topographic histology was assessed according to updated Sydney’s system, and translated into the operative link on gastritis assessment (OLGA), operative link on gastric intestinal metaplasia assessment (OLGIM) stages, and the presence of CGI. SPEM identified by immunostaining of trefoil factor 2 (TFF2) and α5β1 integrin expression were assessed and correlated to the genotype of SNPs within the GCF and verified in GCA patients.

Results: Both GCA patients and their 1st-degree relatives (1st-degree GCF) had 3-3.4 folds higher prevalence of CGI than the DU controls (p< 0.05). Of the 1st-degree GCF, the presence of CGI increased 5.5 folds risk of SPEM and 5.7 folds of advanced SPEM (p< 0.05). CGI also correlated to corpus shift of bacterial densities and integrin α5β1 apical distribution. The combined genotypes ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA was more frequent seen in the GCF than in the DU patients
(p< 1x10-4), and predisposed to a 5.3-fold risk of SPEM in the H. pylori-infected GCF (p= 0.016). Such risk of getting SPEM increased to 112 folds, if combined with either or both of RUNX3+492A and TFF2-308CC (p= 1x10-4). The prevalence of CGI tended to decrease in the GCA patients in descending order from no precancerous lesion, SPEM only, with both IM and SPEM (82%), and IM only (p< 0.05). GCA patients without precancerous lesion and with SPEM only had high prevalence of CGI and tended to have younger age, female predominant, tumor more frequently located at the corpus than the antrum, more advanced in stage and poorer differentiation (p< 0.05). Within these GCA patients, the presence patterns of IM and/or SPEM were closely correlated between the tumor part and non-tumor parts (p< 0.001). The GCF with integrin α5β1 apical distribution at corpus had 8.8 folds-increase risk of advanced SPEM and 29 folds-increase frequency of ITGB1-685-/C/ITGB1-1660AATTT/AATTT/ITGB1+32492G than those without (p= 0.007). This study also found the non-CGI GCA patients with IM only were more frequent to have combinations of SNPs ITGA5-1160GG/TFF2+4649GG, and COX-2+8473TT or MMP-9-1562CC than the DU controls (p< 0.05).

Conclusions: CGI can be early marker to identify H. pylori-infected subjects with high GCA risks. The combined SNPs of ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA predisposed to GCA and may serve as markers to identify high-risk subjects for early H. pylori eradication. Moreover, addition of RUNX3+492A or TFF2-308CC this combined SNPs would greatly facilitate SPEM development. In those without CGI, combined SNPs ITGA5-1160GG/TFF2+4649GG and COX-2+8473TT or MMP-9-1562CC may offer potential rescue markers worth further investigation.
論文目次 摘要 .......i
Abstract ......iv
Acknowledgement .....vii
Table of contents .....ix
List of tables ......xv
List of Figures .....xviii
Abbreviations .....xx
1. Chapter 1: Introduction .....1
1.1 Gastric cancer and H. pylori as a WHO type 1 carcinogen .......1
1.1.1 Gastric cancer control should be focused on early detection, primary and secondary prevention ..1
1.1.2 H. pylori as a WHO type 1 carcinogen ...1
1.1.3 H. pylori eradication to prevent gastric cancer ..2
1.2 The histology subtypes and pre-cancerous progression of gastric cancer .....3
1.2.1 The histology subtypes of gastric cancer .......3
1.2.2 The precancerous lesions in gastric carcinogenesis .4
1.2.3 The pathological markers to screen high gastric cancer risk patients .....5
1.3 To study gastric cancer relatives for high risk host factors predisposing to gastric carcinogenesis ...5
1.3.1 Gastric cancer relatives have high risk for gastric cancer .......6
1.3.2 Identify candidate single nucleotide polymorphisms (SNPs) indicating high gastric cancer risks ..7
1.4 Study goals ......8
2. Chapter 2: Corpus-predominant gastritis index (CGI) may serve as an early marker of H. pylori-infected patients at risk of gastric cancer .....11
2.1 Methods ......11
2.1.1 Patients and study design ....11
2.1.2 Endoscopy and topographic gastric histology grading ......12
2.1.3 OLGA, OLGIM and CGI ....12
2.1.4 TFF2 immunohistochemistry for SPEM grading .13
2.1.5 Immunohistochemistry for integrin α5β1 ...14
2.1.6 Statistics .....15
2.2 Results ......15
2.2.1 Patients enrolled in the study ...15
2.2.2 Histological features by the updated Sydney system among the study groups .....15
2.2.3 Distributions of OLGA stage, OLGIM stage and CGI in the different groups .....16
2.2.4 Presence of CGI correlated to SPEM in the 1st-degree GCF ......17
2.2.5 CGI correlated to H. pylori densities and apical distribution of integrin α5β1 ....17
2.3 Discussions ......18
2.4 Figures and tables .....22
2.4.1 Figures ......22
2.4.2 Tables .....27
3. Chapter 3: Genomic single nucleotide polymorphisms in the offspring of gastric cancer patients predispose to spasmolytic polypeptide-expressing metaplasia after H. pylori infection .....32
3.1 Methods ......32
3.1.1 Patients and study design ....32
3.1.2 Blood sampling and SNP identification .....33
3.1.3 Endoscopy and topographic gastric histology grading ......34
3.1.4 TFF2 immunohistochemistry for SPEM ...35
3.1.5 Statistics .....36
3.2 Results ......37
3.2.1 The differences in the selected SNPs between GCF and DU .......37
3.2.2 Combined predisposing SNPs to differentiate between GCF and DU .......37
3.2.3 The combined SNPs correlated to SPEM in children of GCA ......38
3.2.4 Combined SNPs predisposed to SPEM among different familial relative groups of GCA ....39
3.3 Discussions ......39
3.4 Figures and tables .....45
3.4.1 Figures ......45
3.4.2 Tables .....47
4. Chapter 4: CGI can specifically correlate to the precancerous phenotypes in gastric carcinogenesis ..58
4.1 Methods ......58
4.1.1 Patients and study design ....58
4.1.2 Endoscopy and topographic gastric histology grading ......59
4.1.3 Identify SPEM with H&E stain and TFF2 immunohistochemistry .....59
4.1.4 Blood sampling, integrin α5β1 SNPs identification, and immunohistochemical stains for α5β1 integrin .60
4.1.5 Statistics .....61
4.2 Results ......61
4.2.1 CGI correlated to different subgroups of GCA patients defined by SPEM/IM features at the non-tumor parts .62
4.2.2 The SPEM/IM features at tumor parts and non-tumor parts were closely correlated within GCA patients ..62
4.2.3 The SPEM/IM features at tumor parts correlated to different tumor types and proliferation in GCA patients .63
4.2.4 The presence of CGI correlated to pre-cancerous lesion presentation in children of GCA patients .......63
4.2.5 Integrin α5β1 apical distribution at corpus associated with advanced SPEM and ITGB1 SNPs in children of GCA patients .....64
4.3 Discussions ......65
4.4 Figures and tables .....71
4.4.1 Figures ......71
4.4.2 Tables .....78
5. Chapter 5: Can non-invasive SNPs help to identify the high gastric cancer risk patients without CGI? ...88
5.1 Methods ......88
5.1.1 Patient selection and study design ...88
5.1.2 Blood sampling and SNPs identification ...89
5.1.3 Statistics .....89
5.2 Results ......90
5.2.1. Difference of SNPs in ITGA5, ITGB1, IL-10, COX-2, MMP-9/TIMP-1, RUNX3 and TFF2 among the GCA patients with IM only, the spouses and DU patients ....90
5.2.2. The distribution of the identified SNPs between GCA patients with IM only and the DU patients ..90
5.3 Discussions ......91
5.4 Figures and tables .....94
5.4.1 Figures ......94
5.4.2 Tables .....95
6. Chapter 6: Summary and conclusions ...101
6.1 Summary .....101
6.1.1 Defined CGI as a novel pathological marker for high GCA risk earlier than the current defined pre-cancerous lesions as atrophy and IM .....101
6.1.2 Identified one set of combined SNPs predisposing to SPEM in GCF .....102
6.1.3 CGI could correlate to different pre-cancerous progression phenotypes and earlier to the expressions and SNPs of integrin α5β1 .....103
6.1.4 To identify possible rescue SNPs predisposing to those GCA patients with IM only and less prevalence of CGI .......104
6.2 Applications and conclusions ....104
References ......106
Publication List ......116
Award .......117
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