本文選題：胃癌 + 遺傳變異　； 參考：《南京醫(yī)科大學》2017年博士論文

【摘要】：背景與目的:我國是胃癌的高負擔國家。據(jù)最新統(tǒng)計數(shù)據(jù)顯示,胃癌在我國男性腫瘤發(fā)病率中位居第二位,僅次于肺癌;在女性中位列第三位,僅次于乳腺癌和肺癌。盡管早期胃癌經(jīng)手術(shù)治療后,五年生存率達到90%左右,但早期胃癌往往缺乏典型臨床癥狀,大多數(shù)患者確診時已進入中晚期,錯過最佳治療時期,導(dǎo)致胃癌在人群中的死亡率較高(胃癌占腫瘤死因的第二位)。闡明影響胃癌發(fā)生相關(guān)危險因素,并積極采取三級預(yù)防控制措施對防治胃癌發(fā)生具有重要的公共衛(wèi)生學意義。胃癌是一種與環(huán)境密切相關(guān)的腫瘤。幽門螺旋桿菌感染、腌制食品、硝酸鹽、多環(huán)芳烴化合物、煙草與酒精等暴露都被證實與胃癌的發(fā)生有關(guān)。近年來,有越來越多的研究表明,處于相同的環(huán)境暴露下,不同遺傳背景的個體之間胃癌的易感性也存在差異,說明遺傳因素也是影響胃癌發(fā)生的重要因素。這種遺傳性差異在人群中更多的表現(xiàn)為單核苷酸多態(tài)性(SNP)。全基因組關(guān)聯(lián)研究(GWAS)是一種高效的用于篩選遺傳易感位點的研究策略,相關(guān)胃癌GWAS 發(fā)現(xiàn) 3q13.31(rs9841504)、5p13.1(rs13361707)區(qū)域是中國人群胃癌的易感區(qū)域。但GWAS陽性位點大多位于無生物學功能的區(qū)域,對此存在的統(tǒng)計學關(guān)聯(lián)仍然難以解釋;此外GWAS通常采用較高的統(tǒng)計學檢驗水準(P10-7),假陰性的出現(xiàn)難以避免。與此同時,基于候選基因的研究策略研究胃癌的易感性,尤其是對關(guān)鍵致癌/抑癌基因的易感性研究在闡述胃癌的發(fā)生發(fā)展過程具有十分重要的作用。腫瘤細胞干性特征模型表現(xiàn)為具有自我更新的潛能,也用于解釋許多腫瘤表型。盡管腫瘤干性概念仍有爭議,但Wnt信號在正常和腫瘤干細胞功能方面的重要作用已得到普遍的認同。相對于前體細胞而言,干細胞具有更高的增生能力,且壽命延長,這樣就有更多的機會累積遺傳以及表觀遺傳變異,從而導(dǎo)致腫瘤的發(fā)生。在利用Wnt信號完成自我更新和修復(fù)的組織中,當信號出現(xiàn)異常激活,腫瘤就會產(chǎn)生,這一點在結(jié)直腸癌中已被充分證實。雖然Wnt信號在胃癌發(fā)生中的作用機制研究沒有結(jié)直腸癌中那么地全面和深入,但是在胃癌中普遍存在該信號的異常激活,并與腫瘤進展和轉(zhuǎn)移有關(guān)。和其他重要的信號通路一樣,Wnt信號被一系列拮抗因子和激動因子調(diào)節(jié)以維持動態(tài)平衡。Dickkopfs(DKKs)和 secreted frizzled-related proteins(sFRPs)是Wnt信號通路中重要的胞外抑制因子,分別可以與信號受體(LRP)和配體(Wnt)結(jié)合,通過阻礙配體-受體復(fù)合體形成的方式下調(diào)Wnt信號。基因遺傳變異,尤其是潛在功能區(qū)域變異與腫瘤發(fā)生風險關(guān)系已得到越來越多的研究者關(guān)注。在腎癌、膀胱癌以及乳腺癌中發(fā)現(xiàn)DKKs和sFRPs遺傳變異(SNP)與腫瘤發(fā)生風險有顯著性關(guān)聯(lián)。但DKKs和sFRPs遺傳變異與胃癌的發(fā)生風險有無關(guān)聯(lián),目前尚未見報道。本研究擬采用病例-對照研究設(shè)計等方法探討DKKs與sFRPs基因功能區(qū)域多態(tài)性與胃癌的風險關(guān)系以及相關(guān)遺傳變異可能的生物學作用。同時,利用癌癥基因圖譜 The Cancer Genome Altas(TCGA)胃腺癌項目(TCGA-STAD)公開的RNA-seq數(shù)據(jù)初步探討DKKs與sFRPs在胃癌發(fā)生發(fā)展中的作用,并通過胃癌新發(fā)病例組織標本進行驗證。本研究可以從概率論因果觀的角度為胃癌發(fā)病分子機理研究提供更多的理論依據(jù)。研究對象與方法:本研究設(shè)計首先采用基于醫(yī)院的病例-對照研究。病例組為經(jīng)組織病理學確診的原發(fā)性胃癌;患者來源于江蘇省中醫(yī)院;對照來源于江蘇省中醫(yī)院體檢中心,排除癌癥、重大器質(zhì)性病變、嚴重消化系統(tǒng)疾病。收集時間均為2008年1月到2012年7月。以DKK(1-4)以及sFRP1為候選基因,利用NCBI(https://www.ncbi.nlm.nih.gov/projects/SNP/)篩選位于潛在功能區(qū)域(5' 非翻譯區(qū)、外顯子以及3'非翻譯區(qū)),且在北京漢族人群(Han Chinese in Beijing,HCB)最小等位基因頻率10%的位點。對于位于3'非翻譯區(qū)位點,利用在線SNP功能分析預(yù)測網(wǎng)站 SNPinfo(http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm)選擇吉布斯自由能(Energy)絕對值大于20的miRNA;構(gòu)建pGL3-promoter-SNP重組質(zhì)粒,合成miRNA模擬物(mimics)及陰性對照miRNA(negative control)。將包含不同等位基因的質(zhì)粒及內(nèi)對照質(zhì)粒PRL-SV40瞬時轉(zhuǎn)染至人胃癌細胞株MGC803中同時共轉(zhuǎn)染miRNA模擬物或陰性對照miRNA,使用雙熒光素酶報告基因檢測試劑盒檢測各組螢火蟲/海腎熒光相對比值,探討miRNA與SNP位點間的調(diào)控關(guān)系。我們基于癌癥基因圖譜The Cancer Genome Altas(TCGA)(https://gdc-portal.nci.nih.gov/),TCGA-STAD 項目 RNA-seq 數(shù)據(jù),并聯(lián)合患者人口學信息、臨床病理學特征探討DKKs和sFRP1在胃癌與癌旁組織樣本中mRNA表達量的差異以及mRNA表達對預(yù)后的影響,并利用胃癌新發(fā)病例組織樣本進行驗證,初步推測DKKs和sFRP1在胃癌發(fā)生和預(yù)后中潛在的生物學功能。病例組和對照組間人口學特征比較采用t檢驗和χ2檢驗;擬合優(yōu)度χ2檢驗用于分析各SNP在對照人群中是否符合Hardy-Weinberg平衡;多因素Logistic回歸模型用于計算年齡與性別調(diào)整的比值比(OR值)及其95%可信區(qū)間;采用Bonferroni法進行組內(nèi)多重比較校正;采用基于χ2分布的Q檢驗估計各亞組間的異質(zhì)性;PHASE2.0用于單倍型的構(gòu)建;Quanto software用于統(tǒng)計學把握度的計算;TCGA數(shù)據(jù)整合和轉(zhuǎn)換采用Perl腳本。運用SPSS21.0(International Business Machines Corp.,IBM)進行數(shù)據(jù)管理,SAS 9.1.3(SAS Institute,Inc.,Cary,NC,USA)軟件進行統(tǒng)計分析。研究結(jié)果:1、本研究在DKKs中共篩選出6個SNP位點:rs2241529(AG)、rs3733635(TC)、rs17037102(GA)、rs419764(CT)、rs3206824(GA)、rs2073664(CT)。對這六個SNP位點在病例組和對照組中分別進行基因分型,并沒有發(fā)現(xiàn)兩組間存在顯著性的差異(P0.05)。2、sFRP1中篩選出2個位于3'非翻譯區(qū)的SNP位點rs1127379和rs10088390。sFRP1rs1127379三種基因型(AA、AG、GG)在對照組中的分布頻率為37.1%、46.1%以及16.8%;在病例組中為42.7%、46.3%以及11.0%。經(jīng)雙側(cè)χ2檢驗,發(fā)現(xiàn)這三種基因型在病例組與對照組中的分布有顯著的統(tǒng)計學差異(χ2=7.652,P=0.022)。經(jīng)調(diào)整年齡性別后,Logistic回歸模型分析發(fā)現(xiàn)與AA基因型相比較,攜帶GG基因型與胃癌風險的降低顯著相關(guān)(OR=0.53,95%CI:0.35-0.81);同時,與攜帶A等位基因的個體(AA/AG)相比,隱性模型亦與胃癌風險的降低顯著關(guān)聯(lián)(OR=0.55,95%CI:0.37-0.81)�；谘芯康臉颖竞�,檢測到OR=0.53的統(tǒng)計學把握度達到91.66%,OR=0.55時的統(tǒng)計學把握度為88.66%。把握度計算相關(guān)參數(shù)設(shè)置為:rs1127379的G等位基因頻率為0.4530,胃癌中國人群患病率估計(31.8/100000),遺傳模型則為隱性模型。3、對胃癌的病理類型和原發(fā)部位進行分層分析,rs1127379這種保護性作用在腸型胃癌(OR=0.53,95%CI:0.34-0.84)與非賁門型胃癌中(OR=0.52,95%CI:0.33-0.82)仍然存在的。而在彌漫型胃癌與賁門癌中則未發(fā)現(xiàn)這種顯著性關(guān)聯(lián)(P0.05)。4、根據(jù)年齡、性別、吸煙和飲酒狀況進行分層,進一步探討分析rs1127379位點的風險效應(yīng)。研究發(fā)現(xiàn)無論是高齡組還是低齡組,攜帶GG基因型的個體與攜帶A等位基因的個體相比,均與胃癌風險的降低顯著相關(guān)(低齡組:調(diào)整OR=0.50,95%CI:0.26-0.94;高齡組:調(diào)整 OR=0.57,95%CI:0.35-0.94),且兩者之間同質(zhì)性較好(異質(zhì)性檢驗P=0.66)。在男性中,攜帶GG基因型個體與胃癌風險的降低顯著相關(guān)(調(diào)整OR=0.46,95%CI:0.29-0.73);在飲酒者中,與胃癌風險的下降具有顯著性的關(guān)聯(lián)(調(diào)整OR=0.26,95%CI:0.08-0.88);在吸煙者中,GG基因型亦與胃癌風險的降低具有顯著的關(guān)聯(lián)(調(diào)整OR=0.21,95%CI:0.09-0.47)。5、sFRP13'非翻譯區(qū)SNPrs10088390三種基因型CC、CG、GG在病例和對照組的分布分別為35.1%、47.0%、17.9%以及37.0%、46.9%、16.1%。兩組之間分布經(jīng)雙側(cè)χ2檢驗無顯著性統(tǒng)計學差異(P=0.708)。6、利用PHASE 2.0將sFRP1兩個位于3'非翻譯區(qū)的SNP位點rs1 127379與rs10088390構(gòu)建單倍型。結(jié)果推斷出4種單倍型,分別是Ars1127379Crs10088390,Ars1127379Grs10088390,Grs1127379Grs10088390 以及 Grs1127379Crs10088390。與頻數(shù)最多的 A rs1127379C rs10088390 相比,A rs1127379Grs10088390 與胃癌風險升高具有顯著關(guān)聯(lián)(OR=2.54,95%CI:1.76-3.67)。7、通過SNPinfo預(yù)測網(wǎng)站發(fā)現(xiàn)miRNA-1182可特異性地與sFPR1 rs1127379位點A等位基因結(jié)合,且吉布斯自由能絕對值大于20。采用雙熒光報告基因?qū)嶒炋接憁iRNA-1182與rs1127379 AG位點間的調(diào)控關(guān)系。結(jié)果顯示sFRP1 rs1127379 AG改變可影響miRNA1182對其的調(diào)控作用。8、癌癥基因圖譜TCGA 27對胃癌與癌旁組織mRNA表達差異比較發(fā)現(xiàn)DKK2 mRNA在胃癌組織中的表達水平顯著地高于相應(yīng)的癌旁組織(P=0.007);DKK4mRNA在胃癌組織中的表達水平則顯著地低于相應(yīng)的癌旁組織(P0.0001);DKK1和DKK3 mRNA表達水平在癌組織與癌旁組織中無明顯差異(P0.05)。生存分析發(fā)現(xiàn)DKK1低表達組的五年生存率顯著的高于高表達組(P=0.0086)。sFRP1mRNA在胃癌組織中的表達水平顯著地低于相應(yīng)的癌旁組織(P0.0001),利用7對胃癌新發(fā)病例對sFRP1 mRNA在胃癌和癌旁組織中的差異進行驗證,并未發(fā)現(xiàn)兩組間存在顯著差異(P0.05)。研究結(jié)論:①DKKs潛在功能性SNP位點(rs2241529(AG)、rs3733635(TC)、rs17037102(GA)、rs419764(CT)、rs3206824(GA)、rs2073664(CT))可能與胃癌的發(fā)生風險無顯著性關(guān)聯(lián),同時未發(fā)現(xiàn)這些SNP位點與人口學特征、胃癌病理分型以及發(fā)病部位有關(guān);②sFRP1 rs10088390(CG)多態(tài)與胃癌發(fā)病風險沒有顯著性關(guān)聯(lián);③sFRP1rs1127379GG基因型與腸型胃癌以及非賁門胃癌的發(fā)生風險有關(guān),且該位點改變可影響miRNA-1182對其的調(diào)控水平;④TCGA的研究結(jié)果表明DKKs與sFRP1在胃癌發(fā)生發(fā)展中起一定的生物學作用。然而,sFRP1可能抑制胃癌的作用在7對新發(fā)胃癌組織中并未體現(xiàn),提示其具有種族異質(zhì)性。Wnt信號拮抗因子中的遺傳易感性位點與胃癌的發(fā)生風險有關(guān),對其進行研究有助于我們進一步認識信號拮抗因子在腫瘤發(fā)生發(fā)展中的作用,并為腫瘤高危人群預(yù)防策略提供生物標志物。
[Abstract]:Background and objective: China is the country of high burden of gastric cancer. According to the latest statistics, gastric cancer ranks the second highest in the incidence of male cancer in China, second only to lung cancer; it ranks third among women, second only to breast cancer and lung cancer. Although the five year survival rate of early gastric cancer is about 90%, but early gastric cancer is often lacking. For the typical clinical symptoms, most patients have entered the middle and late stages of diagnosis and miss the best period of treatment, which leads to the high mortality rate of gastric cancer in the population (second of the causes of cancer death). It illustrates the risk factors affecting the occurrence of gastric cancer and actively adopt the three level prevention and control measures to prevent and control the occurrence of gastric cancer. Gastric cancer is a kind of cancer closely related to the environment. Helicobacter pylori infection, pickled food, nitrate, polycyclic aromatic hydrocarbons, tobacco and alcohol have been proved to be related to the occurrence of gastric cancer. In recent years, more and more studies have shown that under the same environmental exposure, individuals with different genetic backgrounds have gastric cancer. There are also differences in susceptibility, indicating that genetic factors are also an important factor affecting the occurrence of gastric cancer. The genetic diversity is more characterized by single nucleotide polymorphisms (SNP). The whole genome association study (GWAS) is a highly efficient research strategy for screening genetic susceptibility loci, and related gastric cancer GWAS is found to be 3q13.31 (rs9841504 The 5p13.1 (rs13361707) region is a susceptible region of gastric cancer in Chinese population. But most of the GWAS positive loci are located in the area without biological function, and the statistical correlation is still difficult to explain. In addition, the GWAS usually uses a higher statistical test level (P10-7), and the appearance of the false negative is difficult to avoid. The study of the susceptibility to gastric cancer, especially the susceptibility to the key carcinogenic / tumor suppressor genes, plays an important role in explaining the development of gastric cancer. The tumor cell dry feature model shows the potential of self renewal and is also used to explain many tumor forms. Although the concept of tumor stem is still controversial, Wnt The important role of signal in normal and tumor stem cell function has been widely recognized. Compared with the precursor cells, the stem cells have higher proliferative capacity and longer life span, so there are more opportunities for accumulation of heredity and epigenetic variation, resulting in swelling of the tumor. The use of Wnt signal to complete self renewal and In the repaired tissues, when the signal is abnormal activation, the tumor is produced, which has been fully confirmed in the colorectal cancer. Although the mechanism of the Wnt signal in the occurrence of gastric cancer is not so comprehensive and deep in colorectal cancer, the abnormal activation of the signal is common in the gastric cancer, and it is associated with the progression and metastasis of the tumor. As with other important signaling pathways, Wnt signals are regulated by a series of antagonistic and excitant factors to maintain dynamic equilibrium.Dickkopfs (DKKs) and secreted frizzled-related proteins (sFRPs), an important extracellular inhibitory factor in the Wnt signaling pathway, which can be combined with the signal receptor (LRP) and ligand (Wnt), by blocking the ligand - The way the receptor complex is formed is down-regulation of Wnt signals. Genetic variations, especially potential functional regional variations and the risk of cancer, have attracted more and more attention. There is a significant association between the DKKs and sFRPs genetic variations (SNP) in renal, bladder and breast cancers (SNP). But DKKs and sFRPs inheritance There is no correlation between the variation and the risk of gastric cancer. This study intends to use case control study design to explore the relationship between the DKKs and sFRPs gene functional regional polymorphism and the risk of gastric cancer, as well as the possible biological effects of the related genetic variation. At the same time, the cancer gene map The Cancer Genome Altas (TCGA) stomach is used. Adenocarcinoma project (TCGA-STAD) open RNA-seq data preliminarily explore the role of DKKs and sFRPs in the development of gastric cancer, and verify the tissue specimens of new cases of gastric cancer. This study can provide more theoretical basis for the study of molecular mechanism of gastric cancer from the perspective of probability theory. First, a case control study based on a hospital was used. The case group was a histologically confirmed primary gastric cancer; the patients were derived from Jiangsu Province Traditional Chinese Medicine Hospital; the controls were derived from the medical center of the hospital, excluding cancer, major organic lesions, and serious digestive diseases. The collection time was from January 2008 to July 2012. DKK (1-4) And sFRP1 as a candidate gene, using NCBI (https://www.ncbi.nlm.nih.gov/projects/SNP/) screening in potential functional regions (5'untranslated region, exon and 3' non translation region), and in the Beijing Han population (Han Chinese in Beijing, HCB) minimum allele frequency 10%. For the 3'non translation site, the use of online SNP work SNPinfo (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm) can be used to select the miRNA of the absolute value of Gibbs free energy (Energy) greater than 20; construct pGL3-promoter-SNP recombinant plasmid, synthesize miRNA analogue (mimics) and negative control miRNA (negative control). Plasmid containing different alleles and PRL-S plasmid PRL-S V40 transiently transfected to human gastric cancer cell line MGC803 co transfected miRNA analogue or negative control miRNA, using double luciferase reporter gene detection kit to detect the relative fluorescence ratio of firefly / sea kidney, and explore the regulatory relationship between miRNA and SNP loci. We based on the cancer gene map The Cancer Genome Altas (TCGA) (https:/) /gdc-portal.nci.nih.gov/), TCGA-STAD project RNA-seq data, combined with demographic information, and clinicopathological features, to explore the difference of mRNA expression in the samples of gastric cancer and para cancer tissue and the effect of mRNA expression on the prognosis of the gastric carcinoma and sFRP1, and to validate the new case group samples of gastric cancer, and preliminarily speculate that DKKs and sFRP1 are in the form of sFRP1. The potential biological function in the occurrence and prognosis of gastric cancer. The demographic characteristics of the case group and the control group were compared with the t test and the chi 2 test. The goodness of fit chi 2 test was used to analyze whether the SNP was in the Hardy-Weinberg balance in the control population; the multifactor Logistic regression model was used to calculate the ratio Ratio of age to sex adjustment (OR value) and its 95 % confidence interval; Bonferroni method is used to carry out multiple comparison correction in group; Q test based on x 2 distribution is used to estimate the heterogeneity among subgroups; PHASE2.0 is used for haplotype construction; Quanto software is used for statistical assurance calculation; TCGA data integration and conversion uses Perl scripts. International Business Machines Co is used. RP., IBM) for data management, SAS 9.1.3 (SAS Institute, Inc., Cary, NC, USA) software to carry out statistical analysis. The results are as follows: 1 Genotyping, no significant difference was found between the two groups (P0.05).2, and 2 SNP loci rs1127379 and rs10088390.sFRP1rs1127379 genotypes (AA, AG, GG) in the non translated region of 3'(AA, AG, GG) were found in the control group for 37.1%, 46.1% and 16.8% in the control group, and 42.7%, 46.3%, and 11.0%. were examined by bilateral chi 2 in the case group. It was found that the distribution of the three genotypes in the case group and the control group was statistically significant (x 2=7.652, P=0.022). After the adjustment of age, the Logistic regression model found that compared with the AA genotype, the GG genotype was significantly related to the decrease of the risk of gastric cancer (OR=0.53,95%CI:0.35-0.81); meanwhile, the A allele was carried with the A allele. Compared with the individual (AA/AG), the recessive model was also significantly associated with the reduction of the risk of gastric cancer (OR=0.55,95%CI:0.37-0.81). Based on the sample content of the study, the statistical assurance of OR=0.53 was 91.66%, and the statistical assurance of OR=0.55 was set as the G allele frequency of rs1127379 with the frequency of the G allele of rs1127379 was 0.4530. The prevalence of gastric cancer in Chinese population is estimated (31.8/100000), and the genetic model is a recessive model of.3. The pathological types and primary sites of gastric cancer are stratified. The protective effect of rs1127379 is still existing in the intestinal gastric carcinoma (OR=0.53,95%CI:0.34-0.84) and non cardial gastric carcinoma (OR= 0.52,95%CI:0.33-0.82), and in diffuse gastric cancer and in the diffuse type of gastric cancer. This significant association (P0.05).4 was not found in the carcinoma of the cardia. The risk effect of rs1127379 loci was further explored according to age, sex, smoking and alcohol consumption. The study found that the risk of gastric cancer was lower than the risk of gastric cancer compared with the individuals carrying the A allele in both the elderly and the younger groups. Significant correlation (low age group: adjusted OR=0.50,95%CI:0.26-0.94; older age group: adjusting OR=0.57,95%CI:0.35-0.94) and better homogeneity (heterogeneity test P=0.66). In men, GG genotype individuals were significantly associated with the decrease in the risk of gastric cancer (adjusting OR= 0.46,95%CI:0.29-0.73); in drinkers, the risk of gastric cancer decreased Significant association (adjusted OR=0.26,95%CI:0.08-0.88); in smokers, the GG genotype was also significantly associated with the reduction of the risk of gastric cancer (adjusted OR=0.21,95%CI:0.09-0.47).5. The SNPrs10088390 three genotypes of CC, CG, and GG in the non translated region of sFRP13'were 35.1%, 47%, 17.9%, and 37%, 46.9%, 16.1%. two, respectively. There was no significant statistical difference between groups (P=0.708).6, and PHASE 2 was used to construct haplotypes of sFRP1 two SNP loci RS1 127379 in 3'non translation region with rs10088390, and the results were deduced from 4 haplotypes, Ars1127379Crs10088390, Ars1127379Grs10088390, Grs1127379Grs10088390, and Grs1127379Crs100. 88390. compared with the most frequent A rs1127379C rs10088390, A rs1127379Grs10088390 has a significant association with the risk of gastric cancer (OR=2.54,95%CI:1.76-3.67).7. Through SNPinfo prediction, miRNA-1182 is found to be specifically associated with sFPR1 rs1127379 loci and A alleles, and the absolute value of Gibbs free energy is greater than 20. using double fluores. The regulation relationship between miRNA-1182 and rs1127379 AG loci was investigated by the light report gene experiment. The results showed that the sFRP1 rs1127379 AG change could affect the regulation of miRNA1182 on it, and the cancer gene map TCGA 27 showed that the expression level of DKK2 mRNA in the gastric cancer group was significantly higher than that of the mRNA expression in the para cancer tissues. The expression level of DKK4mRNA in gastric cancer tissue was significantly lower than that of the corresponding para cancerous tissue (P0.0001), and the expression level of DKK1 and DKK3 mRNA was not significantly different between the cancer tissue and the para cancer tissue (P0.05). The survival analysis found that the five year survival rate of the low expression group of DKK1 was significantly higher than that of the high expression group (P=0.0086).SFRP1mRNA in the stomach. The expression level in cancer tissues was significantly lower than that of the corresponding para cancerous tissue (P0.0001). 7 new cases of gastric cancer were used to verify the difference in sFRP1 mRNA in gastric and paracancerous tissues, and there was no significant difference between the two groups (P0.05). Conclusions: (1) DKKs potential active SNP (rs2241529 (AG), rs3733635 (TC), rs17037102 (GA)) S419764 (CT), rs3206824 (GA), rs2073664 (CT)) may have no significant correlation with the risk of gastric cancer, and the SNP loci are not found to be associated with demographic characteristics, pathological types of gastric cancer and the pathogenesis of gastric cancer; (2) sFRP1 rs10088390 (CG) polymorphism is not associated with the risk of gastric cancer; (3) sFRP1rs1127379GG genotypes and intestinal type gastric cancer are not found. It is related to the risk of non cardia gastric cancer and the change of this loci can affect the regulation of miRNA-1182. 4. The results of TCGA study showed that DKKs and sFRP1 played a certain biological role in the development of gastric cancer. However, the effect of sFRP1 on gastric cancer may not be reflected in 7 NEW gastric cancers, suggesting that it has a racial heterogeneity. The genetic susceptibility loci of sex.Wnt signal antagonists are related to the risk of gastric cancer.
【學位授予單位】：南京醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.2

【相似文獻】

相關(guān)期刊論文 前10條

1 戴成雨;胃癌20例誤診分析[J];實用醫(yī)學雜志;2002年03期

2 李秋波,陶智慧,胡奎,韓智,馬勇;胃癌術(shù)前區(qū)域動脈灌注化療加手術(shù)聯(lián)合治療的療效觀察(附24例)[J];航空航天醫(yī)藥;2003年03期

3 倪海濱,毛振彪,黃介飛,肖明兵,季穎林,張彥亮,冒海蕾;血清可溶性細胞間粘附分子-1與胃癌臨床意義的研究[J];南通醫(yī)學院學報;2003年01期

4 邢亞莉;姚春霞;唐曉君;劉春梅;;彩超在胃癌診斷中的價值[J];基層醫(yī)學論壇;2007年17期

5 ;日本專家用新技術(shù)提高胃癌診斷準確率[J];生物醫(yī)學工程與臨床;2009年02期

6 ;新技術(shù)能提高胃癌診斷準確率[J];中華中醫(yī)藥學刊;2009年07期

7 高春光;;胃癌患者的臨床治療體會[J];中國民族民間醫(yī)藥;2009年14期

8 高瑞鳳;朱曄;劉興姣;;37例進展期胃癌的超聲分析[J];中國實用醫(yī)藥;2010年25期

9 姜可偉;;規(guī)范全球第二大致死率疾病的診斷——《胃癌診斷標準》解讀[J];中國衛(wèi)生標準管理;2010年04期

10 張常華;何裕隆;詹文華;吳英;;多學科小組與胃癌診治[J];現(xiàn)代腫瘤醫(yī)學;2011年06期

相關(guān)會議論文 前10條

1 武淑蘭;魏志杰;殷宇明;;胃癌致微血管病性溶血性貧血的診斷[A];第十一屆全國紅細胞疾病學術(shù)會議暨學習班論文匯編[C];2007年

2 丁濤;;超聲在診斷胃癌中的應(yīng)用[A];中國超聲醫(yī)學工程學會第三屆全國肌肉骨骼超聲醫(yī)學學術(shù)交流會論文匯編[C];2011年

3 陳曉康;呂國榮;蘇若瑟;;應(yīng)用彩色能量多普勒血流顯像對胃癌的診斷價值[A];慶祝中國超聲醫(yī)學工程學會成立20周年——第八屆全國超聲醫(yī)學學術(shù)會議論文匯編[C];2004年

4 于吉人;;胃癌的術(shù)前系統(tǒng)評估[A];2004年浙江省外科學學術(shù)年會論文匯編[C];2004年

5 楊軍樂;寧文德;董季平;徐敏;;多層螺旋CT在胃癌診斷中的應(yīng)用研究[A];中華醫(yī)學會第十三屆全國放射學大會論文匯編（下冊）[C];2006年

6 張曉鵬;;胃癌磁共振成像研究進展[A];第四屆中國腫瘤學術(shù)大會暨第五屆海峽兩岸腫瘤學術(shù)會議教育集[C];2006年

7 張麗紅;常維平;黃賢會;;螺旋CT在特殊部位胃癌診斷中的應(yīng)用[A];中國醫(yī)師協(xié)會放射醫(yī)師分會首屆會員大會暨第四屆醫(yī)學影像山東論壇、山東省第16次放射學會議暨山東省第14屆醫(yī)學影像學學術(shù)研討會論文集[C];2007年

8 陳靜;;彩色多普勒超聲檢查在胃癌的應(yīng)用[A];中國超聲醫(yī)學工程學會第七屆全國腹部超聲學術(shù)會議學術(shù)論文匯編[C];2007年

9 劉池波;梁勇;王海寶;楊林軍;梁津逍;;胃癌患者中血清淀粉樣蛋白A的測定及臨床意義[A];第二屆中國醫(yī)學細胞生物學學術(shù)大會暨細胞生物學教學改革會議論文集[C];2008年

10 吳厚賓;;腹腔鏡在胃癌診治中的應(yīng)用進展(綜述)[A];江西省第二屆胃腸外科學術(shù)會議暨江西省第十二次中西醫(yī)結(jié)合普通外科學術(shù)會議論文匯編[C];2012年

相關(guān)重要報紙文章 前10條

1 錢錚;新技術(shù)能提高胃癌診斷準確率[N];中國中醫(yī)藥報;2009年

2 記者 陳青;胃癌患者從“存活”邁向“樂活”[N];文匯報;2010年

3 李楠;胃癌診斷敏感性從不足30%提高到57.4%[N];健康報;2008年

4 通訊員 李楠;胃癌“轉(zhuǎn)化醫(yī)學”研究見成效[N];上�？萍紙�;2008年

5 記者 楚燕　通訊員 那偉 高樹灼;廈門胃癌研究達國際領(lǐng)先水平[N];廈門日報;2009年

6 胡德榮;新型胃癌分子標志物研究獲突破[N];中國醫(yī)藥報;2010年

7 本報記者 周芳;改善飲食習慣 早發(fā)現(xiàn)早治療[N];吉林日報;2006年

8 中南大學湘雅二醫(yī)院 楊燕貽;胃癌防治有哪些錯誤觀念[N];大眾衛(wèi)生報;2005年

9 特約記者 程守勤;胃癌診斷又有新方法[N];家庭醫(yī)生報;2003年

10 重慶萬州 黃瓊;胃癌的手術(shù)治療[N];上海中醫(yī)藥報;2013年

相關(guān)博士學位論文 前10條

1 孫大志;基于microRNA 21的調(diào)控作用探討從痰論治胃癌的作用機制[D];中國人民解放軍醫(yī)學院;2012年

2 陳悅之;TNFAIP8在胃癌中的表達和對調(diào)節(jié)胃癌細胞增殖，影響侵襲及遷移中的作用研究[D];山東大學;2015年

3 殷繼鵬;腫瘤血管靶向肽GX1用于胃癌的分子影像研究[D];第四軍醫(yī)大學;2015年

4 蔡習強;TFEB介導(dǎo)的自噬在胃癌耐藥中的作用及其機制研究[D];第四軍醫(yī)大學;2015年

5 趙曉迪;microRNA-7調(diào)控胃癌惡性生物學行為的功能與分子機制研究[D];第四軍醫(yī)大學;2015年

6 尚華;MicroRNA-125a在胃癌中表達水平的研究及其臨床意義[D];山東大學;2015年

7 關(guān)中正;TGF-β在胃癌免疫逃逸中作用及機制研究[D];山東大學;2015年

8 黃勇;AEG-1/MT qDH、NF-κB、MMP-9在胃癌中的表達及相關(guān)性的研究[D];山東大學;2015年

9 謝黎明;胃癌中miR-124表達的意義及作用機制研究[D];南華大學;2015年

10 劉佳寧;SOX9和CEACAM1在胃癌組織中表達及其對胃癌細胞增殖和轉(zhuǎn)移的影響[D];山東大學;2015年

相關(guān)碩士學位論文 前10條

1 徐海蓉;胃癌危險因素的流行病學研究[D];南京醫(yī)科大學;2002年

2 張軍利;p27、PTEN與VEGF蛋白在胃癌組織中的表達及其意義[D];泰山醫(yī)學院;2014年

3 馬春婷;胃癌與幽門螺桿菌的相關(guān)性研究[D];石河子大學;2015年

4 王士杰;腹腔鏡手術(shù)治療進展期遠端胃癌的臨床療效及患者術(shù)后隨訪生存質(zhì)量研究[D];中國人民解放軍醫(yī)學院;2015年

5 李浩;胃癌血清蛋白標記物的篩選與鑒定[D];鄭州大學;2015年

6 王巍;胃癌患者血液樣品的光譜分析[D];鄭州大學;2015年

7 李玉博;高場磁共振在胃癌術(shù)前T分期與分級的價值[D];鄭州大學;2015年

8 張?zhí)K鈺;SOX4和P53蛋白在胃癌組織中的表達及貞芪扶正膠囊對胃癌術(shù)后輔助治療作用的觀察[D];蘭州大學;2015年

9 馬來陽;能譜CT成像在胃癌術(shù)前分期及分化程度評價中的應(yīng)用研究[D];蘭州大學;2015年

10 侯向紅;HORMAD2在胃癌中的表達及對胃癌細胞增殖和凋亡的影響[D];蘭州大學;2015年

，

本文編號：1947581