本文選題：結(jié)直腸癌 + 磷酸化　； 參考：《華中科技大學(xué)》2015年博士論文

【摘要】：結(jié)直腸癌是全球的第四大惡性腫瘤。我國每年結(jié)直腸癌的新發(fā)病例數(shù)估計(jì)高達(dá)25萬,且近年來發(fā)病率一直呈現(xiàn)上升趨勢(shì),其防治已刻不容緩。大量流行病學(xué)研究和分子功能學(xué)實(shí)驗(yàn)表明,結(jié)直腸癌是一種由遺傳和環(huán)境長期共同作用引起的復(fù)雜性疾病。目前已揭示的環(huán)境危險(xiǎn)因素包括煙草、酒精、高脂飲食和缺乏鍛煉等。但暴露于相同或相似環(huán)境的人群中,僅有少部分個(gè)體最終進(jìn)展為結(jié)直腸癌,提示機(jī)體遺傳因素在結(jié)直腸癌的易感性中也占據(jù)了重要地位。隨著基因組學(xué)的迅猛發(fā)展,目前結(jié)直腸癌的全基因組關(guān)聯(lián)研究和候選基因研究已鑒定出不少易感區(qū)域和位點(diǎn),但仍不足以填補(bǔ)結(jié)直腸癌遺傳機(jī)制上的空白,亟需我們從更多角度深入挖掘潛在的易感位點(diǎn),幫助構(gòu)建該病的遺傳易感圖譜。 蛋白磷酸化是一種非常重要的真核細(xì)胞翻譯后修飾,幾乎參與了細(xì)胞生命活動(dòng)的各個(gè)環(huán)節(jié),該修飾調(diào)節(jié)系統(tǒng)主要由蛋白激酶(催化磷酸化反應(yīng))、蛋白磷酸酶(催化去磷酸化反應(yīng))和底物蛋白組成。異常的磷酸化調(diào)節(jié)可導(dǎo)致蛋白穩(wěn)定性下降,功能活性異常,進(jìn)而影響細(xì)胞增殖、分化和凋亡等,最終參與疾病發(fā)生。通過整合基因組學(xué)和磷酸化蛋白組學(xué)的數(shù)據(jù),人們已發(fā)現(xiàn)越來越多的磷酸化相關(guān)基因變異與腫瘤有關(guān),并且發(fā)生在激酶、磷酸酶和底物分子上的遺傳變異可顯著影響人群的患癌易感性。目前激酶與腫瘤的研究已近成熟,而磷酸酶／底物與腫瘤的相關(guān)研究雖然取得一定成果,但我們對(duì)其的認(rèn)識(shí)大多停留在探索階段,亟需更多的人群研究和功能實(shí)驗(yàn)加以闡明。因此,本研究從底物和磷酸酶的角度出發(fā),采用病例-對(duì)照人群研究和生物信息學(xué)分析,佐以功能學(xué)實(shí)驗(yàn)的方法,探索蛋白磷酸化相關(guān)遺傳變異與中國人群結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間的關(guān)聯(lián)。 第一部分磷酸化相關(guān)遺傳變異ADD1-rs4963與結(jié)直腸癌的易感性研究 研究背景：ADD1(α-adducin)蛋白是細(xì)胞骨架的重要組成部分,在細(xì)胞增殖、運(yùn)動(dòng)和通訊中發(fā)揮著重要作用。之前的研究表明,ADD1基因可能對(duì)腫瘤發(fā)生有潛在作用。最近的研究顯示,位于該基因上的磷酸化相關(guān)錯(cuò)義多態(tài)rs4963(Ser586Cys)與非賁門胃癌的發(fā)病風(fēng)險(xiǎn)相關(guān),提示該位點(diǎn)可能對(duì)消化系統(tǒng)腫瘤的遺傳易感性有潛在影響。 研究目的：探索ADD1-rs4963與中國人群結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間的關(guān)聯(lián)；分析基因-環(huán)境交互作用對(duì)結(jié)直腸癌易感性的潛在影響。 研究方法：采用以醫(yī)院為基礎(chǔ)的病例-對(duì)照研究策略,通過主流的TaqMan分型技術(shù)對(duì)納入的1054名原發(fā)性結(jié)直腸癌病例和1128名健康對(duì)照進(jìn)行ADD1-rs4963的基因型別檢測(cè)。采用Pearson's χ2檢驗(yàn)和獨(dú)立樣本t檢驗(yàn)評(píng)價(jià)病例組和對(duì)照間的基本特征分布(包括年齡、性別、吸煙和飲酒)。使用疾病比值比(OR)和95%置信區(qū)間(95%CI)作為效應(yīng)指標(biāo),運(yùn)用非條件logistic回歸分析ADD1-rs4963與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間的關(guān)聯(lián),以及ADD1基因和吸煙(或飲酒)暴露的交互作用。 研究結(jié)果：ADD1-rs4963的等位基因頻率和基因型頻率在結(jié)直腸癌病例組和健康對(duì)照組中均存在統(tǒng)計(jì)學(xué)差異(等位基因頻率比較：P=0.011；基因型頻率比較：P=0.028)。在校正了年齡、性別、吸煙和飲酒因素后,與CC基因型相比,CG基因型和GG基因型的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)分別上升25%(OR=1.25,95%CI=1.02-1.55,P=0.036)和35%(OR=1.35,95%CI=1.06.1.72,P=0.015)；顯性模型顯示,CG和GG基因型個(gè)體發(fā)生結(jié)直腸癌的風(fēng)險(xiǎn)是攜帶CC基因型個(gè)體的1.28倍(OR=1.28,95%CI=1.05-1.57,P=0.014)；加性模型分析發(fā)現(xiàn),每增加一個(gè)G等位基因,結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)增加0.16倍(OR=1.16,95%CI=1.03-1.31,P=0.016)。以上分析提示該位點(diǎn)與結(jié)直腸癌的易感性顯著相關(guān)。我們進(jìn)一步探索了ADD1基因與吸煙/飲酒的交互作用,但未發(fā)現(xiàn)陽性結(jié)果。 研究結(jié)論：位于ADD1基因上的磷酸化相關(guān)遺傳變異rs4963顯著影響了中國人群結(jié)直腸癌的發(fā)病風(fēng)險(xiǎn)。本研究首次報(bào)道了ADD1基因與結(jié)直腸癌的易感性相關(guān),進(jìn)一步促進(jìn)了我們對(duì)結(jié)直腸癌遺傳機(jī)制的理解。 研究創(chuàng)新：首次探索了ADD1基因與中國人群結(jié)直腸癌發(fā)病之間的關(guān)聯(lián),一定程度彌補(bǔ)了國內(nèi)在蛋白磷酸化相關(guān)遺傳變異與腫瘤關(guān)聯(lián)研究的空白。 第二部分經(jīng)典蛋白酪氨酸磷酸酶家族的遺傳錯(cuò)義多態(tài)與結(jié)直腸癌的易感性研究 研究背景：蛋白酪氨酸磷酸酶可拮抗酪氨酸激酶的效應(yīng),維持細(xì)胞內(nèi)酪氨酸蛋白的磷酸化平衡,在調(diào)控細(xì)胞生長、增殖、凋亡和運(yùn)動(dòng)等方面發(fā)揮了十分重要的作用。經(jīng)典蛋白酪氨酸磷酸酶是該大家族中發(fā)現(xiàn)最早、研究最為廣泛的一個(gè)亞類,目前已被報(bào)道與多種人類腫瘤密切相關(guān)。 研究目的：系統(tǒng)評(píng)價(jià)經(jīng)典蛋白酪氨酸磷酸酶基因家族上的遺傳錯(cuò)義多態(tài)與中國人群結(jié)直腸癌發(fā)生風(fēng)險(xiǎn)之間的關(guān)聯(lián)；深入分析候選位點(diǎn)與吸煙／飲酒之間的潛在交互效應(yīng);進(jìn)一步探索陽性位點(diǎn)的生物學(xué)功能,分析其在結(jié)直腸癌發(fā)病中的潛在作用。 研究方法：首先通過生物信息學(xué)系統(tǒng)挖掘經(jīng)典蛋白酪氨酸磷酸酶基因家族上的遺傳錯(cuò)義多態(tài),然后采用兩階段病例-對(duì)照研究分析候選位點(diǎn)與結(jié)直腸癌發(fā)病之間的關(guān)聯(lián),運(yùn)用非條件logistic回歸評(píng)估候選位點(diǎn)在調(diào)整了常見混雜因素(年齡、性別、吸煙和飲酒)后的疾病效應(yīng)值,以及候選基因與環(huán)境暴露之間的交互作用,最后通過蛋白功能實(shí)驗(yàn)進(jìn)一步探索陽性關(guān)聯(lián)位點(diǎn)的潛在生物學(xué)效應(yīng)。 研究結(jié)果：前期篩選一共得到25個(gè)候選位點(diǎn)。第一階段的人群研究共納入1096例結(jié)直腸癌和1816例匹配對(duì)照,其中我們鑒定出2個(gè)陽性位點(diǎn),分別是PTPN12基因上的rs3750050(P-adjusted=2.220×10-4,FDR-adjusted=0.004)和PTPN23基因上的rs6780013(P-adjusted=3.645×10-4,FDR-usted=0.003).我們接著在另一地區(qū)納入的767例結(jié)直腸癌和1215例匹配對(duì)照的人群中對(duì)這2個(gè)位點(diǎn)進(jìn)行了關(guān)聯(lián)研究,發(fā)現(xiàn)PTPNl2-rs750050得到成功驗(yàn)證。合并分析顯示,rs3750050-G是結(jié)直腸癌發(fā)病的風(fēng)險(xiǎn)等位基因,每增加一個(gè)G風(fēng)險(xiǎn)等位基因,結(jié)直腸癌的罹患風(fēng)險(xiǎn)將上升25％(OR=1.25,95％CI=1.14.1.36,P=8.158×10-7).基因-環(huán)境交互分析表明,PTPN12-rs3750050還與吸煙存在顯著交互(P吸煙=0.013),同時(shí)具備GG危險(xiǎn)基因型和吸煙暴露時(shí),其結(jié)直腸癌的發(fā)病風(fēng)險(xiǎn)明顯增高(OR=1.50,95％CI=1.24.1.83).進(jìn)一步的Western Blot結(jié)果揭示,該位點(diǎn)的G風(fēng)險(xiǎn)等位基因可明顯削弱PTPN12蛋白對(duì)下游Src因子的去磷酸化作用,可能在結(jié)直腸癌致病過程中發(fā)揮一定作用。 研究結(jié)論：1.PTPN12基因與中國人群的結(jié)直腸癌易感性相關(guān),rs3750050-G可顯著增加結(jié)直腸癌的發(fā)生風(fēng)險(xiǎn)。 2.PTPN12-rs3750050與吸煙存在顯著的交互作用,吸煙暴露進(jìn)一步增加了危險(xiǎn)基因型攜帶者罹患結(jié)直腸癌的風(fēng)險(xiǎn)。 3.PTPN12-rs3750050影響了PTPN12蛋白的磷酸酶活性,G風(fēng)險(xiǎn)等位基因削弱了該蛋白對(duì)下游重要底物Src的去磷酸化調(diào)節(jié)作用,從而可能在結(jié)直腸癌發(fā)病中發(fā)揮作用。 研究創(chuàng)新：采用生物信息學(xué)、兩階段人群研究結(jié)合蛋白功能實(shí)驗(yàn)的綜合分析策略,首次在中國人群中系統(tǒng)性探討了經(jīng)典PTPs基因家族的遺傳錯(cuò)義多態(tài)與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián),同時(shí)深入分析了相關(guān)基因位點(diǎn)與吸煙或飲酒的交互作用,并通過蛋白功能實(shí)驗(yàn)為發(fā)現(xiàn)的人群關(guān)聯(lián)提供了一定的分子生物學(xué)支持證據(jù)。
[Abstract]:Colorectal cancer is the fourth largest malignant tumor in the world. The number of new cases of colorectal cancer in China is estimated to be up to 250 thousand annually, and the incidence of colorectal cancer has been increasing in recent years. The prevention and control of colorectal cancer has been urgent. A large number of epidemiological studies and molecular functional experiments show that colorectal cancer is caused by a long-term common effect of heredity and environment. The environmental risk factors that are now revealed include tobacco, alcohol, high fat diet, and lack of exercise. But among people exposed to the same or similar environment, only a few individuals eventually progressed to colorectal cancer, suggesting that genetic factors also play an important role in the susceptibility of colorectal cancer. With the rapid development of the genome association and candidate gene research in colorectal cancer, many susceptible regions and loci have been identified, but it is still not enough to fill the gap in the genetic mechanism of colorectal cancer. It is urgent for us to dig into the potential susceptible loci from more angles and help build the genetic susceptibility map of the disease.
Protein phosphorylation is a very important post-translational modification of eukaryotic cells, which almost participates in all aspects of cell life activities. The modification regulation system is mainly composed of protein kinase (catalytic phosphorylation), protein phosphatase (catalytic dephosphorylation) and substrate protein. Abnormal phosphorylation can lead to the decrease of protein stability. Abnormal functional activity, which affects cell proliferation, differentiation and apoptosis, and eventually participates in the disease. By integrating the data of genomics and phosphorylation proteomics, more and more phosphorylation related gene mutations have been found to be associated with tumors, and the genetic variation on the kinase, phosphatase and substrate molecules can be significantly affected. At present, the research on the cancer of the population is sensitive. The research on the kinase and tumor is now mature, while the related research of phosphatase / substrate and tumor has achieved certain results, but most of our understanding of it remains at the exploratory stage, and more population studies and functional experiments are needed to clarify. A case control population study and bioinformatics analysis were used to explore the association between the genetic variation associated with protein phosphorylation and the risk of colorectal cancer in Chinese people.
Part I phosphorylation related genetic variants ADD1-rs4963 and susceptibility to colorectal cancer
Background: ADD1 (alpha -adducin) protein is an important part of the cytoskeleton and plays an important role in cell proliferation, exercise and communication. Previous studies have shown that the ADD1 gene may have potential effects on the occurrence of tumors. Recent studies have shown that the phosphorylation related missense polymorphic rs4963 (Ser586Cys) and non cardia in this gene are located in this gene. The risk of gastric cancer is related to the risk of gastrointestinal cancer.
Objective: To explore the association between ADD1-rs4963 and the risk of colorectal cancer in Chinese people, and to analyze the potential impact of gene environmental interaction on the susceptibility of colorectal cancer.
Methods: a hospital based case-control study was used to detect ADD1-rs4963 genotypes in 1054 cases of primary colorectal cancer and 1128 healthy controls by mainstream TaqMan typing. The basic characteristics of the case group and the control were evaluated by Pearson's chi 2 test and independent sample t test. Distribution (including age, sex, smoking and drinking). Using the ratio of disease ratio (OR) and 95% confidence interval (95%CI) as the effect index, the association between ADD1-rs4963 and the risk of colorectal cancer was analyzed by unconditional logistic regression, and the interaction of ADD1 gene and smoking (or drinking) exposure.
Results: the allele frequency and genotype frequency of ADD1-rs4963 were statistically different in both the colorectal cancer case group and the healthy control group (the allele frequency comparison: P=0.011; genotype frequency comparison: P=0.028). The CG genotype and the GG gene were compared with the CC genotype after the correction of age, sex, smoking and drinking factors. The risk of colorectal cancer was increased by 25% (OR=1.25,95%CI=1.02-1.55, P=0.036) and 35% (OR=1.35,95%CI=1.06.1.72, P=0.015), and the dominant model showed that the risk of colorectal cancer in CG and GG genotypes was 1.28 times that of the CC genotype (OR=1.28,95%CI= 1.05-1.57, P=0.014). The risk of colorectal cancer increased by 0.16 times the G allele (OR=1.16,95%CI=1.03-1.31, P=0.016). The above analysis suggested that the locus was significantly related to the susceptibility to colorectal cancer. We further explored the interaction between ADD1 gene and smoking / drinking, but we did not find the positive results.
Research conclusions: the phosphorylation related genetic variation (rs4963) based on the ADD1 gene significantly affects the risk of colorectal cancer in Chinese population. This study first reports the correlation between the ADD1 gene and the susceptibility to colorectal cancer and further promotes our understanding of the genetic mechanism of colorectal cancer.
Research Innovation: the first exploration of the association between the ADD1 gene and the incidence of colorectal cancer in Chinese population, to a certain extent, has made up for the gap in the study of genetic variation related to protein phosphorylation and the association of tumors in China.
The second part is the genetic missense polymorphism of the classical protein tyrosine phosphatase family and the susceptibility to colorectal cancer.
Background: protein tyrosine phosphatase can antagonize the effect of tyrosine kinase and maintain the phosphorylation of tyrosine protein in cells. It plays a very important role in regulating cell growth, proliferation, apoptosis and movement. It has been reported to be closely related to a variety of human tumors.
Objective: to systematically evaluate the association between the genetic missense polymorphism of the classical protein tyrosine phosphatase gene family and the risk of colorectal cancer in Chinese population; analyze the potential interaction between the candidate loci and smoking / drinking, and further explore the biological function of the positive loci, and analyze it in the pathogenesis of colorectal cancer. The potential effect.
Research methods: first, the genetic missense polymorphism in the classical protein tyrosine phosphatase gene family was excavated by the bioinformatics system. Then the two stage case control study was used to analyze the association between the candidate loci and the incidence of colorectal cancer. The candidate loci were evaluated by the non conditional logistic regression to adjust the common confounding factors. The effects of age, sex, smoking and drinking, as well as the interaction between candidate genes and environmental exposure, and the potential biological effects of positive associated sites were further explored through protein functional experiments.
Results: 25 candidate loci were obtained in the preliminary screening. The first stage population study included 1096 cases of colorectal cancer and 1816 matched controls, of which 2 positive sites were identified, rs3750050 (P-adjusted=2.220 * 10-4, FDR-adjusted= 0.004) on the PTPN12 gene and rs6780013 (P-adjusted=3.645) on PTPN23 gene, respectively. X 10-4, FDR-usted=0.003). We went on to study the 2 loci in 767 cases of colorectal cancer and 1215 matched controls, and found that PTPNl2-rs750050 was successfully verified. The combined analysis showed that rs3750050-G was a risk allele of colorectal cancer, each additional G risk allele, The risk of colorectal cancer will rise by 25% (OR=1.25,95%CI=1.14.1.36, P=8.158 x 10-7). Gene environmental interaction analysis shows that PTPN12-rs3750050 also has a significant interaction with smoking (P smoking =0.013). At the same time, there is a significant increase in the risk of colorectal cancer (OR=1.50,95%CI=1.24.1.83) when there is a GG risk genotype and smoking exposure. One step Western Blot results revealed that the G risk allele of the site could significantly weaken the dephosphorylation of the PTPN12 protein to the downstream Src factor, and may play a role in the pathogenesis of colorectal cancer.
Conclusion: 1.PTPN12 gene is associated with susceptibility to colorectal cancer in Chinese population. Rs3750050-G can significantly increase the risk of colorectal cancer.
There was a significant interaction between 2.PTPN12-rs3750050 and smoking. Exposure to smoking further increased the risk of colorectal cancer in carriers of the risk genotype.
3.PTPN12-rs3750050 affects the activity of the phosphatase of the PTPN12 protein, and the G risk allele weakens the dephosphorylation of the protein, which is an important downstream substrate, Src, and may play a role in the pathogenesis of colorectal cancer.
Research Innovation: the association of the genetic missense polymorphism of the classic PTPs gene family and the risk of colorectal cancer was systematically investigated in Chinese population by bioinformatics, the two stage crowd study combined with the comprehensive analysis of protein function experiments. The protein function test provided some evidence of molecular biology support for the discovery of population association.

【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R735.34

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3 汪一虹;在確定的法國人群中年齡<45歲結(jié)直腸癌病人與≥45歲結(jié)直腸癌病人的比較[J];國外醫(yī)學(xué)(消化系疾病分冊(cè));2002年01期

4 李會(huì)晨;結(jié)直腸癌解剖位置的連續(xù)性右向遷移[J];國外醫(yī)學(xué).外科學(xué)分冊(cè);2003年03期

5 李志霞;結(jié)直腸癌復(fù)發(fā)及轉(zhuǎn)移的綜合治療[J];中華胃腸外科雜志;2003年06期

6 何建苗,蒲永東,曹志宇,劉衛(wèi)平;老年人結(jié)直腸癌186例的外科治療[J];中華胃腸外科雜志;2003年05期

7 保紅平,方登華,高瑞崗,李奎,張雪松,劉天錫;青年人結(jié)直腸癌臨床病理分析[J];中國普外基礎(chǔ)與臨床雜志;2004年01期

8 章江;;監(jiān)測(cè)結(jié)直腸癌非常必要[J];國外醫(yī)學(xué)情報(bào);2004年04期

9 郜文秀,楊艷芳,梁小波,李耀平,李佩珍;細(xì)胞粘附分子變異體在結(jié)直腸癌中的表達(dá)及預(yù)后[J];中國公共衛(wèi)生;2005年07期

10 Nozawa T. ,Enomoto T. ,Koshida Y. ,M. Kuranami,王志宇;人結(jié)直腸癌黏膜下血小板源性內(nèi)皮細(xì)胞生長因子特異性增強(qiáng)表達(dá)[J];世界核心醫(yī)學(xué)期刊文摘(胃腸病學(xué)分冊(cè));2005年06期

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7 王啟遠(yuǎn);周長江;高云飛;徐巖;李坤;;血管內(nèi)皮生長因子與結(jié)直腸癌[A];《中華急診醫(yī)學(xué)雜志》第八屆組稿會(huì)暨急診醫(yī)學(xué)首屆青年論壇論文匯編[C];2009年

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