本文選題：胃癌 + 單核苷酸多態(tài)性　； 參考：《山東大學(xué)》2016年博士論文

【摘要】：胃癌是主要的惡性腫瘤之一,2012年全球估計(jì)新發(fā)胃癌951,600例,病死人數(shù)723,100例,東亞地區(qū)包括中國是胃癌的高發(fā)地區(qū),隨著人口老齡化的加劇,胃癌仍是我國最常見的惡性腫瘤之一,給個(gè)人及家庭帶來了沉重的經(jīng)濟(jì)和精神負(fù)擔(dān)。胃癌發(fā)病隱匿,早期可無任何癥狀或只有一些非特異性的消化道癥狀,早期胃癌診斷率低,臨床就診時(shí),許多患者已發(fā)生局部和／或遠(yuǎn)處轉(zhuǎn)移,進(jìn)展期胃癌的淋巴結(jié)(LN)轉(zhuǎn)移率可達(dá)70%左右,嚴(yán)重影響了手術(shù)和放化療等臨床抗腫瘤綜合治療的療效,患者預(yù)后生存較差。胃癌的發(fā)生和進(jìn)展是一個(gè)多因素參與、多階段進(jìn)展的復(fù)雜過程,是遺傳和環(huán)境因素共同作用的結(jié)果,遺傳易感性和基因-環(huán)境交互作用的相關(guān)研究,有利于高危個(gè)體的篩查和及早干預(yù),最終使患者受益。單核苷酸多態(tài)性(single nucleotide polymorphism,SNP)是一種非常常見的遺傳變異類型,它是染色體DNA中單個(gè)核苷酸轉(zhuǎn)換、顛換等變化所導(dǎo)致的序列多態(tài)性,作為限制性片段長度多態(tài)性以及微衛(wèi)星多態(tài)性后的新一代遺傳標(biāo)記,SNP在高危個(gè)體篩查、易感基因鑒定等方面有著廣泛的應(yīng)用前景。近年來,包括全基因組關(guān)聯(lián)分析(Genome-wide association study, GWAS)在內(nèi)的關(guān)聯(lián)研究表明,許多單核苷酸多態(tài)與腫瘤的易感性有關(guān),最近,一個(gè)納入了824個(gè)研究的大薈萃分析發(fā)現(xiàn)了一些“高質(zhì)量”的胃癌易感位點(diǎn),分析顯示11個(gè)SNP與胃癌的患病風(fēng)險(xiǎn)顯著相關(guān),包括：MUC1 rs2070803, MTX1 rs2075570, PSCA rs2294008, PRKAA1 rs13361707, PLCE1 rs2274223, TGFBR2 rs3087465, PKLR rs3762272, PSCA rs2976392, GSTP1 rs1695, CASP8 rs3834129和TNF rs1799724.不同遺傳背景人群的關(guān)聯(lián)研究,有助于發(fā)現(xiàn)更多與胃癌相關(guān)的重要SNP位點(diǎn)并進(jìn)一步闡明胃癌的易感機(jī)制。近年來歐美人群的全基因組關(guān)聯(lián)研究顯示煙堿型乙酰膽堿受體(nicotinic acetylcholine receptor, nAChR)基因簇的多個(gè)SNP位點(diǎn)與肺癌的患病風(fēng)險(xiǎn)和吸煙行為相關(guān)。吸煙是肺癌、食管癌、胃癌等多種腫瘤的重要危險(xiǎn)因素,煙草中的活性物質(zhì),如4-(甲基亞硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)和N-亞硝基降煙堿(NNN),可作用于尼古丁乙酰膽堿受體,促進(jìn)細(xì)胞增殖及致瘤性轉(zhuǎn)化。nAChR基因簇內(nèi)的尼古丁乙酰膽堿受體基因(cholinergic nicotine receptor genes),比如CHRNA3和CHRNA5,分別編碼nAChR受體蛋白的不同多肽亞基。目前對(duì)nAChR基因簇SNP位點(diǎn)與吸煙相關(guān)腫瘤發(fā)病風(fēng)險(xiǎn)的研究主要集中在肺癌,對(duì)其他吸煙相關(guān)腫瘤,如食管癌、胃癌的研究很少。本單位在前期研究中發(fā)現(xiàn),與從基因型相比,CHRNB3 rs 13280604 GG/AG攜帶者食管鱗癌的患病風(fēng)險(xiǎn)顯著升高(OR=1.44, 95%CI:1.26-1.65, P=8.7×10-8)。CHRNB3 rs13280604 (與rs4950連鎖)與食管鱗癌發(fā)病風(fēng)險(xiǎn)明顯關(guān)聯(lián),但CHRNB3基因的多態(tài)位點(diǎn)是否影響其他吸煙相關(guān)腫瘤如胃癌的易感性,值得進(jìn)一步探討。此外,其他nAChR基因簇多態(tài)位點(diǎn),如CHRNA5 rs667282, CHRNA3 rs3743073,據(jù)報(bào)道在中國漢族人群中與肺癌風(fēng)險(xiǎn)相關(guān),但這些多態(tài)位點(diǎn)與胃癌的關(guān)系,尚有待探討。此外,研究顯示,趨化因子12 (chemokine ligand 12, CXCL12)基因3’UTR區(qū)域的一個(gè)重要多態(tài)位點(diǎn),rs1801157(G801A),可能與CXCL12的表達(dá)有關(guān),與G等位基因相比,rs1801157 A等位基因與CXCL12基因的高表達(dá)相關(guān)。CXCL12,又叫基質(zhì)細(xì)胞衍生因子-1(stromal cell-derived factor-1, SDF-1),通過與趨化因子受體4(chemokine receptor 4, CXCR4))結(jié)合,在腫瘤的生長、進(jìn)展中發(fā)揮著重要作用。既往研究發(fā)現(xiàn),CXCR4陽性的胃癌更易發(fā)生腹膜種植轉(zhuǎn)移,并且CXCR4在分期晚、有淋巴結(jié)轉(zhuǎn)移的胃癌中顯著陽性,轉(zhuǎn)移淋巴結(jié)中SDF-1 mRNA的水平明顯高于正常淋巴結(jié),提示CXCL12/CXCR4在胃癌進(jìn)展中的重要角色。體外實(shí)驗(yàn)還發(fā)現(xiàn),CXCR4在胃癌SGC-7901和MGC-803細(xì)胞系中表達(dá),SDF-1促進(jìn)腫瘤細(xì)胞的增殖,且效應(yīng)呈劑量依賴性。有學(xué)者在T3期結(jié)直腸癌的研究中觀察到,有淋巴結(jié)轉(zhuǎn)移的患者rs1801157GA/AA頻率高于淋巴結(jié)轉(zhuǎn)移陰性者。還有文獻(xiàn)報(bào)道,CXCL12 G801A多態(tài)可能增加乳腺癌和肺癌的患病風(fēng)險(xiǎn)。而且,在采用Kaplan-Meier Plotter在線分析(http://kmplot.com/analvsis/)公共數(shù)據(jù)庫中胃癌CXCL12表達(dá)與患者預(yù)后生存的關(guān)系時(shí),我們發(fā)現(xiàn),與低表達(dá)CXCL12的胃癌患者相比,高表達(dá)CXCL12者總生存和無進(jìn)展生存均較差(Affymetrix probe ID:203666_at)。因此,我們假設(shè)CXCL12 rs1801157 (G801A)多態(tài)可能通過CXCL12/CXCR4通路的作用進(jìn)而影響胃癌的發(fā)生和進(jìn)展,為驗(yàn)證這個(gè)假設(shè),本研究中我們分析了該位點(diǎn)與胃癌發(fā)病風(fēng)險(xiǎn)及淋巴結(jié)轉(zhuǎn)移的關(guān)系。另外,染色體5p15.33區(qū)域是調(diào)節(jié)端粒生物學(xué)功能的重要區(qū)域,該區(qū)域包含兩個(gè)重要的基因：端粒酶反轉(zhuǎn)錄酶(telomerase reverse transcriptase, TERT)和唇腭裂跨膜1樣蛋白基因(cleft lip and palate trans-membrane 1-like,CLPTMIL)。端粒酶由端粒酶逆轉(zhuǎn)錄酶、端粒酶RNA和端粒酶協(xié)同蛋白組成,在端粒的調(diào)節(jié)及染色體完整性的維持中有著重要作用,端粒酶在許多腫瘤組織包括胃癌中都有表達(dá),而正常細(xì)胞在絕大多數(shù)時(shí)候都不表達(dá)或僅少量表達(dá),一些培養(yǎng)的增殖活躍的惡性腫瘤細(xì)胞,也呈現(xiàn)出較高的端粒酶活性。多數(shù)情況下,常見遺傳變異只與特定腫瘤類型風(fēng)險(xiǎn)相關(guān),但包括全基因組關(guān)聯(lián)分析在內(nèi)的多項(xiàng)研究提示,TERT-CLPTM1L區(qū)域的多態(tài)位點(diǎn),比如rs2736098、rs401681,與多種腫瘤的易感性有關(guān)。rs401681是CLPTMIL基因內(nèi)含子區(qū)域的一個(gè)SNP,最近的薈萃分析顯示,攜帶rs401681[T]等位基因者皮膚黑色素瘤、胰腺癌患病風(fēng)險(xiǎn)增高,但罹患膀胱癌、前列腺癌、肺癌等腫瘤的風(fēng)險(xiǎn)降低。此外,有文獻(xiàn)指出,rs401681[C]可能與較短的端粒長度相關(guān)。并且,薈萃分析提示,較短的端粒長度與消化道腫瘤患病風(fēng)險(xiǎn)相關(guān),而且短的端粒長度可能預(yù)示著較差的預(yù)后生存。但是,rs401681多態(tài)位點(diǎn)是否影響國人胃癌的發(fā)生和進(jìn)展,尚缺乏相關(guān)報(bào)道。鑒于以上所述,本課題在前期研究的基礎(chǔ)上,采用病例一對(duì)照研究方法,收集性別與年齡匹配的胃癌和正常對(duì)照外周靜脈血標(biāo)本,共收集了1658例,其中胃癌716例,健康對(duì)照942例,提取各研究對(duì)象的基因組DNA,設(shè)計(jì)、合成單核苷酸多態(tài)位點(diǎn)CHRNA5 rs667282,CHRNA3 rs3743073,CHRNB3 rs4950,CXCL12 rs1801157,TERT-CLPTM1L rs401681的熒光探針和引物,采用TaqMan探針法在ABI 7500 PCR儀上進(jìn)行多態(tài)位點(diǎn)的檢測和基因分型,比較病例組和對(duì)照組基因型頻率分布差異,并結(jié)合問卷調(diào)查及病歷系統(tǒng)收集的相關(guān)資料信息,多元Logistic回歸分析各多態(tài)位點(diǎn)與胃癌發(fā)病風(fēng)險(xiǎn)及淋巴結(jié)轉(zhuǎn)移的關(guān)系。本研究中,所有研究對(duì)象均為中國漢族人群,胃癌患者為病理確認(rèn)的胃腺癌患者,對(duì)照組來自醫(yī)院查體中心的健康人群,我們采用TaqMan探針法對(duì)上述多態(tài)位點(diǎn)成功進(jìn)行了基因分型,對(duì)照組中各SNP基因型分布均符合Hardy-Weinberg平衡(P0.05)。我們發(fā)現(xiàn),CHRNB3 rs4950在病例組和對(duì)照組中基因型分布有顯著統(tǒng)計(jì)學(xué)差異(P=0.006),其TT CT.CC基因型頻率在病例組中分別為54.6%、39.8%和5.6%,在對(duì)照組中分別為62.1%、34.1%和3.8%。Logistic回歸分析顯示,在校正了性別、年齡、吸煙和飲酒因素后,SNP rs4950 CT/CC基因型攜帶者胃癌患病風(fēng)險(xiǎn)明顯高于TT基因型者(CT/CC vs. TT:OR=1.346,95% CI=1.101-1.645, P=0.004; CT vs. TT:OR=1.311,95% CI=1.065-1.614,P=0.011:CC vs.TT:OR=1.688,95% CI=1.050一2.715,P=0.031).通過亞組分層分析我們發(fā)現(xiàn),在男性組、非飲酒組中,攜帶CHRNB3 rs4950 CT/CC基因型者罹患胃癌的風(fēng)險(xiǎn)明顯增加,CT/CC基因型在吸煙組和不吸煙組均增加胃癌的患病風(fēng)險(xiǎn),在年齡分層中,小于等于60歲和大于60歲者發(fā)病風(fēng)險(xiǎn)相似。而對(duì)于CHRNA5 rs667282,CHRNA3 rs3743073,CXCL12 rs1801157及TERT-CLPTM1L rs401681,病例組和對(duì)照組基因型分布無明顯差異(P值分別為0.565、0.541、0.604和0.532),Logistic回歸也未發(fā)現(xiàn)這四個(gè)多態(tài)位點(diǎn)與胃癌易感性相關(guān)。此外,在有淋巴結(jié)轉(zhuǎn)移資料的630例胃癌患者中,我們分析了各多態(tài)位點(diǎn)與胃癌淋巴結(jié)(LN)轉(zhuǎn)移風(fēng)險(xiǎn)的關(guān)系,我們發(fā)現(xiàn),在胃癌淋巴結(jié)轉(zhuǎn)移組和無淋巴結(jié)轉(zhuǎn)移組中,CHRNA5 rs667282,CHRNA3 rs3743073,CHRNB3 rs4950及TERT-CLPTM1L rs401681基因型頻率分布無統(tǒng)計(jì)學(xué)差異,但是,CXCL12 rs1801157多態(tài)在淋巴結(jié)轉(zhuǎn)移組和無淋巴結(jié)轉(zhuǎn)移組中基因型分布有明顯差異,其GG、GA、AA基因型頻率在兩組中分別為47.9%、43.6%、8.6%和58.8%、35.2%、6.0%,與CXCL12 rs1801157 GG基因型相比GA、GA/AA基因型攜帶者胃癌淋巴結(jié)轉(zhuǎn)移風(fēng)險(xiǎn)增高GA vs.GG OR=1.521,95% CI=1.080-2.143,P=0.016；GA/AA vs.GG OR=1.555,95% CI=1.121-2.156,P=0.008),在調(diào)整了年齡、性別、吸煙及飲酒狀態(tài)后,該多態(tài)位點(diǎn)與胃癌淋巴結(jié)轉(zhuǎn)移風(fēng)險(xiǎn)的相關(guān)性仍然顯著(GA vs.GG OR=1.506,95% CI=1.067-2.126,P=0.020；GA/AA vs.GG OR=1.555,95% CI=1.119-2.162, P=0.009；A vs.G OR=1.410,95% CI=1.084-1.834,P=0.010)。綜上所述,通過包含1658例研究對(duì)象的病例一對(duì)照研究,我們發(fā)現(xiàn)CHRNB3 rs4950 CT/CC基因型顯著增加中國北方漢族人群胃癌的發(fā)病風(fēng)險(xiǎn)。另外,CXCL12 rs1801157多態(tài)雖然不影響胃癌的易感性,但其GA/AA基因型攜帶者胃癌淋巴結(jié)轉(zhuǎn)移風(fēng)險(xiǎn)明顯增加。本研究提示SNP在高風(fēng)險(xiǎn)個(gè)體篩查中的潛在應(yīng)用價(jià)值,但是,SNP關(guān)聯(lián)研究仍需要大樣本、不同遺傳背景人群的驗(yàn)證以及后續(xù)的功能學(xué)實(shí)驗(yàn)研究。
[Abstract]:Gastric cancer is one of the main malignant tumors. In 2012, 951600 cases of new gastric cancer were estimated, 723100 cases were dead, the region of East Asia including China was the high incidence of gastric cancer. With the increasing aging of the population, gastric cancer was still one of the most common malignant tumors in China, which brought heavy economic and spiritual burden to individuals and families. There is no symptoms or only some nonspecific symptoms of digestive tract in the early stage. The diagnosis rate of early gastric cancer is low. In clinical treatment, many patients have local and / or distant metastasis. The lymph node (LN) transfer rate of advanced gastric cancer is about 70%, which seriously affects the curative effect of comprehensive antitumor treatment such as surgery and radiotherapy and chemotherapy. The prognosis of the patients is poor. The occurrence and progress of gastric cancer is a multi factor participation, the complex process of multistage progress is the result of the combination of genetic and environmental factors. Genetic susceptibility and gene environment interaction are related to the screening and early intervention of high-risk individuals, and the patients benefit from single nucleotide polymorphisms. (single nucleotide polymorphism, SNP) is a very common genetic variation type, which is the sequence polymorphism caused by the change of single nucleotide transformation and transformation in chromosome DNA, as a new generation marker after restriction fragment length polymorphism and microsatellite polymorphism, SNP in high-risk individuals screening, susceptibility gene identification, and so on. In recent years, association studies, including Genome-wide association study (GWAS), have shown that many single nucleotide polymorphisms are associated with tumor susceptibility. Recently, a large meta analysis included in 824 studies found some "high quality" gastric cancer susceptibility loci. The correlation between the 11 SNP is associated with the risk of gastric cancer, including MUC1 rs2070803, MTX1 rs2075570, PSCA rs2294008, PRKAA1 rs13361707, PLCE1 rs2274223. More important SNP loci associated with gastric cancer and further elucidate the susceptibility mechanism of gastric cancer. In recent years, all genomic association studies in European and American populations have shown that the multiple SNP loci of the nicotinic acetylcholine receptor (nicotinic acetylcholine receptor, nAChR) gene cluster are related to the risk of lung cancer and smoking behavior. Smoking is a lung cancer and esophageal cancer. An important risk factor for a variety of cancers such as gastric cancer, such as 4- (methyl nitrosamine) -1- (3- pyridyl) -1- butanone (NNK) and N- nitronicotine (NNN), can act on nicotine acetylcholine receptor, promote cell proliferation and tumorigenic.NAChR gene cluster of nicotinic acetylcholine receptor gene (cholinergic NIC). Otine receptor genes), such as CHRNA3 and CHRNA5, encode the different peptide subunits of the nAChR receptor protein, respectively. The current studies on the risk of nAChR gene cluster SNP sites and smoking related tumors are mainly concentrated in lung cancer, and there are few studies on other smoking related tumors, such as esophageal cancer, and gastric cancer. The risk of esophageal squamous cell carcinoma in CHRNB3 RS 13280604 GG/AG carriers increased significantly (OR=1.44, 95%CI:1.26-1.65, P=8.7 x 10-8).CHRNB3 rs13280604 (and rs4950 linkage), which was significantly associated with the risk of esophageal squamous cell carcinoma, but the polymorphic loci of the CHRNB3 gene were worthy of the susceptibility to other smoking related tumors, such as gastric cancer. In addition, other polymorphic loci of nAChR gene cluster, such as CHRNA5 rs667282 and CHRNA3 rs3743073, are reported to be associated with lung cancer risk in Chinese Han population, but the relationship between these polymorphic loci and gastric cancer remains to be discussed. Furthermore, the study shows that chemokine 12 (chemokine ligand 12, CXCL12) gene is an important part of the 3 'UTR region. The polymorphic loci, rs1801157 (G801A), may be related to the expression of CXCL12. Compared with the G allele, the rs1801157 A allele is associated with the high expression of the CXCL12 gene, also called the matrix cell derivative -1 (stromal cell-derived factor-1), by combining with chemokine receptor 4 (G). Previous studies have shown that CXCR4 positive gastric cancer is more likely to occur in peritoneal metastasis, and CXCR4 is significantly positive in gastric cancer with lymph node metastasis in late stages, and the level of SDF-1 mRNA in the metastatic lymph nodes is significantly higher than that in the normal lymph nodes, suggesting that CXCL12/CXCR4 plays an important role in the progression of gastric cancer. It was also found that CXCR4 was expressed in the SGC-7901 and MGC-803 cell lines of gastric cancer, and SDF-1 promoted the proliferation of tumor cells, and the effect was dose-dependent. In the study of T3 stage colorectal cancer, some scholars have observed that the frequency of rs1801157GA/AA in patients with lymph node metastasis is higher than that of lymph node metastases. There is also a literature report that the CXCL12 G801A polymorphism is possible. Increase the risk of breast cancer and lung cancer. Moreover, we found that the total survival and progression free survival of those with high expression of CXCL12 were poorer than those with low expression of CXCL12 in the Kaplan-Meier Plotter online analysis (http://kmplot.com/analvsis/) public database. Metrix probe ID:203666_at). Therefore, we hypothesized that the CXCL12 rs1801157 (G801A) polymorphism may affect the occurrence and progress of gastric cancer through the role of the CXCL12/CXCR4 pathway. In order to verify this hypothesis, we have analyzed the relationship between the site and the risk of gastric cancer and lymph node metastasis. In addition, the chromosome 5p15.33 area is a regulation. An important region of telomere biological function, which contains two important genes: the telomerase reverse transcriptase (telomerase reverse transcriptase, TERT) and the cleft lip and palate transmembrane 1 protein gene (cleft lip and palate trans-membrane 1-like, CLPTMIL). Telomerase is composed of telomerase reverse transcriptase, telomerase RNA and telomerase synergetic protein group It plays an important role in the regulation of telomere and the maintenance of the integrity of chromosomes. Telomerase is expressed in many tumor tissues, including gastric cancer, while normal cells are not expressed or only a small amount of expression in most cases. Some of the cultured malignant tumor cells also exhibit higher telomerase activity. The common genetic variation is only associated with a specific tumor type risk, but a number of studies, including full genome association analysis, suggest that the polymorphic loci in the TERT-CLPTM1L region, such as rs2736098, rs401681, are associated with a variety of tumor susceptibility,.Rs401681 is a SNP in the intron of the CLPTMIL gene, and recent meta-analysis shows that the polymorphic loci of the CLPTMIL gene are carried. The risk of rs401681[T] allele skin melanoma and pancreatic cancer is higher, but the risk of bladder, prostate and lung cancer is lower. In addition, the literature suggests that rs401681[C] may be associated with shorter telomere length. And a meta-analysis suggests that shorter telomere length is associated with the risk of gastrointestinal cancer, and Short telomere length may indicate poor prognosis. However, there are no reports on whether rs401681 polymorphic loci affect the occurrence and progression of human gastric cancer. A total of 1658 cases were collected, including 716 cases of gastric cancer and 942 healthy controls. The genomic DNA of each study object was extracted, designed to synthesize the single nucleotide polymorphic loci CHRNA5 rs667282, CHRNA3 rs3743073, CHRNB3 rs4950, CXCL12 rs1801157, TERT-CLPTM1L rs401681 fluorescent probes and primers. The TaqMan probe method was used on the 7500 detector. The polymorphism loci were detected and genotyping, and the difference of genotype frequency distribution between the case group and the control group was compared, and the correlation data collected by the questionnaire survey and the medical record system were combined with the multiple Logistic regression analysis of the polymorphic loci and the relationship between the risk of gastric cancer and the lymph node metastasis. All the research subjects were Chinese Han. In the population, gastric cancer patients were confirmed as gastric adenocarcinoma, and the control group was from the healthy population of the hospital check-up center. We used the TaqMan probe to genotyping the polymorphic loci successfully. The distribution of SNP genotypes in the control group was consistent with the Hardy-Weinberg balance (P0.05). We found that CHRNB3 rs4950 was in the case group and the control group. The genotype distribution in the group was significantly different (P=0.006), and the TT CT.CC genotype frequency was 54.6%, 39.8% and 5.6% in the case group. The 62.1%, 34.1% and 3.8%.Logistic regression analysis in the control group showed the risk of gastric cancer in the SNP rs4950 CT/CC genotype carriers after the correction of sex, age, smoking and drinking factors. It was significantly higher than the TT genotype (CT/CC vs. TT:OR=1.346,95% CI=1.101-1.645, P=0.004; CT vs. TT:OR=1.311,95% CI=1.065-1.614, P=0.011:CC vs.TT:OR=1.688,95%). We found that the risk of gastric cancer in the male, non drinking group and the non drinkers group Significantly increased, CT/CC genotype increased the risk of gastric cancer in both smoking and non smoking groups. In age stratification, the risk of onset was similar to those aged 60 and 60 years old. For CHRNA5 rs667282, CHRNA3 rs3743073, CXCL12 rs1801157 and TERT-CLPTM1L rs401681, there was no significant difference in genotype distribution between the case group and the control group (P values, respectively. For 0.565,0.541,0.604 and 0.532), the four polymorphic loci were not found to be associated with the susceptibility to gastric cancer in Logistic regression. In addition, in 630 cases of gastric cancer with lymph node metastasis, we analyzed the relationship between the polymorphic loci and the risk of lymph node (LN) metastasis of gastric cancer. We found that the lymph node metastasis and lymph node metastasis groups were in the gastric cancer. The frequency distribution of CHRNA5 rs667282, CHRNA3 rs3743073, CHRNB3 rs4950 and TERT-CLPTM1L rs401681 genotype was not statistically different, but the polymorphism of CXCL12 rs1801157 polymorphism was significantly different in the lymph node metastasis group and the non lymph node metastasis group. The frequency of GG, GA, and genotype was 47.9%, 43.6%, 8.6% and 58.8%, 35.2%, respectively, in the two groups. 6%, compared with the CXCL12 rs1801157 GG genotype GA, the risk of lymph node metastasis of gastric cancer in the GA/AA genotype carriers increased GA vs.GG OR=1.521,95% CI=1.080-2.143, P=0.016, GA/AA vs.GG, and after adjusting the age, sex, smoking and drinking state, the polymorphic loci were associated with the risk of lymph node metastasis of gastric cancer. The correlation is still significant (GA vs.GG OR=1.506,95% CI=1.067-2.126, P=0.020; GA/AA vs.GG OR=1.555,95% CI=1.119-2.162, P=0.009; A vs.G). The risk of gastric cancer in the Han population. In addition, although CXCL12 rs1801157 polymorphism does not affect the susceptibility of gastric cancer, the risk of lymph node metastasis in the GA/AA genotype carriers is significantly increased. This study suggests the potential application value of SNP in high-risk individual screening, but the SNP study still needs large samples and different genetic backgrounds. Verification and subsequent functional experimental research.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.2

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