MicroRNA單核苷酸多態(tài)性與肝細胞癌易感性及MiR-196a2rs11614913與肝癌預后相關性研究
發(fā)布時間：2019-04-08 20:32
【摘要】：第一部分Micro RNA單核苷酸多態(tài)性與肝細胞癌易感性目的:本文擬采用自然人群為基礎病例對照研究,旨在揭示位于mi RNA編碼區(qū)和作用靶點的基因多態(tài)性與肝癌發(fā)病風險可能的關系。綜合分析并揭示環(huán)境因素、遺傳因素與mi RNA的交互作用對肝癌發(fā)病風險的影響。并根據(jù)肝癌遺傳易感性的分析結(jié)果,探討mi RNA不同基因型在易感患者血腫的的表達特性,為臨床對于肝癌預防性診斷提供參考。方法:隨機選取內(nèi)蒙古醫(yī)科大學附屬醫(yī)院2013年9月-2016年2月266例肝細胞癌患者作為實驗組,266例來我院體檢的正常無癌病人為對照組。統(tǒng)計實驗組的性別、年齡、高血壓、糖尿病、吸煙、飲酒、病毒感染、腫瘤大小和腫瘤階段。收集兩組患者靜脈血5m L樣品,通過聚合酶鏈式反應限制性片段多態(tài)性試劑盒,進行測量;通過聚合酶鏈反應對DNA擴增。mi R-146a2 rs2910164,mi R-196a2rs11614913,mi R-149 rs2292832和mi R-499 rs3746444的基因型,通過RT-PCR法進行擴增,擴增后全部測序。通過病例對照研究,綜合評估各個基因多態(tài)性與肝癌遺傳易感性的關系,并計算相應的比值比和95%可信區(qū)間。結(jié)果:(1)本研究發(fā)現(xiàn)高血壓、糖尿病、吸煙與患肝癌風險差異無統(tǒng)計學意義。飲酒和病毒感染與肝癌發(fā)病風險顯著相關。(2)對位于mi RNA編碼區(qū)的基因多態(tài)性與肝癌發(fā)病風險關系的分析結(jié)果表明,mi R-196(TT基因型和T等位基因基因)編碼區(qū)的基因多態(tài)性位點與肝癌的發(fā)病風險顯著增加,分別增加了2.29倍和1.60倍(95%CI=1.11-2.32),而mi R-146、mi R-149和mi R-499的多態(tài)性與肝癌危險性不相關。(3)HBV感染者mi R-196a2(CT+TT基因型)可能是增加肝細胞癌的危險性的原因,性別、年齡和酒精中毒mi R-196的多態(tài)性和肝細胞癌危險性之間可能沒有相關性。結(jié)論:(1)mi R-196a2 rs11614913的TT基因型和T等位基因與肝細胞癌危險性增加有顯著相關性,該兩種基因型可能成為肝細胞癌的診斷的標記。(2)HBV感染顯著影響mi R-196a2 rs11614913的多態(tài)性與肝細胞癌危險性之間的關系。(3)mi R-196a2 rs11614913的TT基因型和T等位基因可能是肝細胞癌患病危險性增加的標記。(4)mi R-196a2 rs11614913的多態(tài)性可能是影響肝細胞癌的發(fā)展的因素之一,特別是感染HBV的患者。第二部分Mi R-196a2rs11614913多態(tài)性與肝癌預后關系的研究目的:由實驗一可以發(fā)現(xiàn)Mi R-196a的多態(tài)性與肝癌的發(fā)病可能相關,本部分的研究就Mi R-196a基因多態(tài)性與原發(fā)性肝癌預后相關指標之間的相關性進行分析,旨在為指導肝細胞癌化療藥物的治療和評估患者的預后及生存時間提供可能的參考。方法:隨機選取2013年9月-2016年2月123例肝細胞癌內(nèi)蒙古醫(yī)科大學附屬醫(yī)院肝細胞癌患者作為實驗組。研究對象采用RT-PCR方法檢測其Mi R-196a2rs11614913基因多態(tài)性;采用基因計數(shù)方法檢驗對象等位基因頻率和基因型頻率。藥物治療組:肝癌術(shù)后手術(shù)后1個月選用FOLFOX(奧沙利鉑+亞葉酸鈣+氟尿嘧啶)聯(lián)合治療,全部患者均愿意在手術(shù)后接受化療,術(shù)前后基線資料均從臨床病例中獲得,病人出院后每隔四周電話隨訪或者門診隨訪,直到患者死亡或本次研究結(jié)束。對比基線資料,觀察Mi R-196a2rs11614913基因多態(tài)性類型,對比Mi R-196a2rs11614913基因多態(tài)性檢測情況。結(jié)果:選取123例肝癌患者中,90例(73.2%)腫瘤直徑小于5cm,33例(26.8%)腫瘤直徑大于5cm,47例(38.2%)顯示為腫瘤TNM分期中的II期,76例(61.8%)顯示為III-IV期。Mi R-196a基因型在化療藥物敏感組和不敏感組間差異有統(tǒng)計學意義(χ2=11.91,P=0.001)。與Mi R-196a功能基因型相比較,Mi R-196a缺陷基因型患者生存時間較長,差異具有統(tǒng)計學意義。Mi R-196a基因缺陷型顯著降低了肝癌的病死風險,HR(95%CI)為0.49(0.25-0.96)。結(jié)論:(1)Mi R-196a2rs11614913的多態(tài)性與患者對化療藥物敏感性和生存時間相關。而與Mi R-196a2rs11614913功能型相比較,Mi R-196a2rs11614913的缺陷型基因型的肝癌患者對化療藥物更敏感。(2)Mi R-196a2rs11614913基因型患者基因型生存期短。(3)Mi R-196a2rs11614913多態(tài)性陽性的患者可以為患者制定個性化的化療方案提供參考。
[Abstract]:Objective: To study the relationship between the polymorphism of the first partial micro-RNA and the susceptibility of hepatocellular carcinoma: a case-control study based on the natural population is proposed to reveal the possible relationship between the gene polymorphism of the mi-RNA coding region and the target of action and the risk of liver cancer. The effects of environmental factors, genetic factors and the interaction of mi-RNA on the risk of liver cancer were analyzed. According to the analysis result of the genetic susceptibility of the liver cancer, the expression characteristics of the mi-RNA different genotypes in the susceptible patients haematoma are discussed, and the reference for the preventive diagnosis of the liver cancer is provided for clinic. Methods: From September 2013 to February 2016,266 cases of hepatocellular carcinoma were randomly selected as experimental group and 266 cases of normal non-cancer patients in our hospital as the control group. The sex, age, hypertension, diabetes, smoking, drinking, viral infection, tumor size and tumor stage of the experimental group were counted. The 5-m L samples from the venous blood of the two groups were collected and measured by the restriction fragment polymorphism kit of the polymerase chain reaction; and the DNA was amplified by the polymerase chain reaction. The genotype of mi R-146a2 rs2910164, mi R-196a2rs11614913, mi R-149rs2292832 and mi R-499 rs374644 was amplified by RT-PCR and all sequenced after amplification. The relationship between each gene polymorphism and the genetic susceptibility of the liver cancer was assessed by a case-control study, and the corresponding ratio ratio and the 95% confidence interval were calculated. Results: (1) There was no significant difference in the risk of hypertension, diabetes, smoking and the risk of liver cancer. Alcohol consumption and viral infection were associated with the risk of liver cancer. (2) The results of the analysis of the relationship between the gene polymorphism and the risk of liver cancer in the mi-RNA coding region show that the genetic polymorphism site of the mi R-196 (TT genotype and T allele gene) coding region is increased by 2.29 times and 1.60 times (95% CI = 1.11-2.32), and the mi R-146, respectively. The polymorphisms of mi R-149 and mi R-499 are not associated with the risk of liver cancer. (3) The mi R-196a2 (CT + TT genotype) of HBV-infected persons may be the cause of increasing the risk of hepatocellular carcinoma, and there may be no correlation between the polymorphism of the mi R-196 and the risk of hepatocellular carcinoma. Conclusion: (1) The TT genotype and T allele of mi R-196 a2 rs11614913 are significantly associated with the increase of the risk of hepatocellular carcinoma, which may be a marker of the diagnosis of hepatocellular carcinoma. (2) The relationship between the polymorphism of mi R-196 a2 rs11614913 and the risk of hepatocellular carcinoma was significantly affected by HBV infection. (3) The TT genotype and T allele of mi R-196 a2 rs11614913 may be an increased risk for hepatocellular carcinoma. (4) The polymorphism of mi R-196 a2 rs11614913 may be one of the factors that affect the development of hepatocellular carcinoma, especially those with HBV. The study of the relationship between the polymorphism of the second part Mi R-196a2rs11614913 and the prognosis of the liver cancer is to study the correlation between the polymorphism of the Mi R-196a and the prognosis of the primary liver cancer. It is intended to provide a possible reference for the treatment and evaluation of the prognosis and survival time of a patient with a chemotherapeutic agent for hepatocellular carcinoma. Methods: From September 2013 to February 2016,123 patients with hepatocellular carcinoma from Inner Mongolia Medical University of Inner Mongolia were selected as experimental group. The gene polymorphism of Mi R-196 a2rs11614913 was detected by RT-PCR. The treatment group: FOLFOX (oxaliplatin + calcium folinate + fluorouramide) was used in the first month after the operation of the liver cancer. All the patients were willing to receive the chemotherapy after the operation, and the baseline data before and after the operation were obtained from the clinical cases. The patient was followed up for follow-up or out-of-patient follow-up every four weeks after the discharge of the patient until the patient died or the study was completed. The genetic polymorphism of the Mi R-196a2rs11614913 gene was observed compared with the baseline data, and the genetic polymorphism of the Mi R-196a2rs11614913 gene was compared. Results: Of the 123 patients with liver cancer,90 (73.2%) of the tumors had a tumor diameter of less than 5 cm,33 (26.8%) of the tumors had a tumor diameter of more than 5 cm, and 47 (38.2%) were shown as phase II in the TNM stage of the tumor and 76 (61.8%) were shown as phase III-IV. The difference of Mi R-196a genotype between sensitive and non-sensitive groups was statistically significant (Sup2 = 11.91, P = 0.001). Compared with the functional genotype of the Mi R-196a, the survival time of the Mi R-196a deficient genotype was longer and the difference was of statistical significance. The genetic defect of Mi R-196a significantly reduced the risk of dying of liver cancer, and HR (95% CI) was 0.49 (0.25-0.96). Conclusion: (1) The polymorphism of Mi R-196a2rs11614913 is related to the sensitivity and survival time of chemotherapy drugs. In contrast to the functional phase of the Mi R-196 a2rs11614913, the patients with a defective genotype of Mi R-196a2rs11614913 were more sensitive to chemotherapy. (2) The genotype of the Mi R-196a2rs11614913 genotype was short. (3) Patients with the Mi R-196a2rs11614913 polymorphism can provide a reference for the patient to develop a personalized chemotherapy regimen.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R735.7
本文編號：2454902
[Abstract]:Objective: To study the relationship between the polymorphism of the first partial micro-RNA and the susceptibility of hepatocellular carcinoma: a case-control study based on the natural population is proposed to reveal the possible relationship between the gene polymorphism of the mi-RNA coding region and the target of action and the risk of liver cancer. The effects of environmental factors, genetic factors and the interaction of mi-RNA on the risk of liver cancer were analyzed. According to the analysis result of the genetic susceptibility of the liver cancer, the expression characteristics of the mi-RNA different genotypes in the susceptible patients haematoma are discussed, and the reference for the preventive diagnosis of the liver cancer is provided for clinic. Methods: From September 2013 to February 2016,266 cases of hepatocellular carcinoma were randomly selected as experimental group and 266 cases of normal non-cancer patients in our hospital as the control group. The sex, age, hypertension, diabetes, smoking, drinking, viral infection, tumor size and tumor stage of the experimental group were counted. The 5-m L samples from the venous blood of the two groups were collected and measured by the restriction fragment polymorphism kit of the polymerase chain reaction; and the DNA was amplified by the polymerase chain reaction. The genotype of mi R-146a2 rs2910164, mi R-196a2rs11614913, mi R-149rs2292832 and mi R-499 rs374644 was amplified by RT-PCR and all sequenced after amplification. The relationship between each gene polymorphism and the genetic susceptibility of the liver cancer was assessed by a case-control study, and the corresponding ratio ratio and the 95% confidence interval were calculated. Results: (1) There was no significant difference in the risk of hypertension, diabetes, smoking and the risk of liver cancer. Alcohol consumption and viral infection were associated with the risk of liver cancer. (2) The results of the analysis of the relationship between the gene polymorphism and the risk of liver cancer in the mi-RNA coding region show that the genetic polymorphism site of the mi R-196 (TT genotype and T allele gene) coding region is increased by 2.29 times and 1.60 times (95% CI = 1.11-2.32), and the mi R-146, respectively. The polymorphisms of mi R-149 and mi R-499 are not associated with the risk of liver cancer. (3) The mi R-196a2 (CT + TT genotype) of HBV-infected persons may be the cause of increasing the risk of hepatocellular carcinoma, and there may be no correlation between the polymorphism of the mi R-196 and the risk of hepatocellular carcinoma. Conclusion: (1) The TT genotype and T allele of mi R-196 a2 rs11614913 are significantly associated with the increase of the risk of hepatocellular carcinoma, which may be a marker of the diagnosis of hepatocellular carcinoma. (2) The relationship between the polymorphism of mi R-196 a2 rs11614913 and the risk of hepatocellular carcinoma was significantly affected by HBV infection. (3) The TT genotype and T allele of mi R-196 a2 rs11614913 may be an increased risk for hepatocellular carcinoma. (4) The polymorphism of mi R-196 a2 rs11614913 may be one of the factors that affect the development of hepatocellular carcinoma, especially those with HBV. The study of the relationship between the polymorphism of the second part Mi R-196a2rs11614913 and the prognosis of the liver cancer is to study the correlation between the polymorphism of the Mi R-196a and the prognosis of the primary liver cancer. It is intended to provide a possible reference for the treatment and evaluation of the prognosis and survival time of a patient with a chemotherapeutic agent for hepatocellular carcinoma. Methods: From September 2013 to February 2016,123 patients with hepatocellular carcinoma from Inner Mongolia Medical University of Inner Mongolia were selected as experimental group. The gene polymorphism of Mi R-196 a2rs11614913 was detected by RT-PCR. The treatment group: FOLFOX (oxaliplatin + calcium folinate + fluorouramide) was used in the first month after the operation of the liver cancer. All the patients were willing to receive the chemotherapy after the operation, and the baseline data before and after the operation were obtained from the clinical cases. The patient was followed up for follow-up or out-of-patient follow-up every four weeks after the discharge of the patient until the patient died or the study was completed. The genetic polymorphism of the Mi R-196a2rs11614913 gene was observed compared with the baseline data, and the genetic polymorphism of the Mi R-196a2rs11614913 gene was compared. Results: Of the 123 patients with liver cancer,90 (73.2%) of the tumors had a tumor diameter of less than 5 cm,33 (26.8%) of the tumors had a tumor diameter of more than 5 cm, and 47 (38.2%) were shown as phase II in the TNM stage of the tumor and 76 (61.8%) were shown as phase III-IV. The difference of Mi R-196a genotype between sensitive and non-sensitive groups was statistically significant (Sup2 = 11.91, P = 0.001). Compared with the functional genotype of the Mi R-196a, the survival time of the Mi R-196a deficient genotype was longer and the difference was of statistical significance. The genetic defect of Mi R-196a significantly reduced the risk of dying of liver cancer, and HR (95% CI) was 0.49 (0.25-0.96). Conclusion: (1) The polymorphism of Mi R-196a2rs11614913 is related to the sensitivity and survival time of chemotherapy drugs. In contrast to the functional phase of the Mi R-196 a2rs11614913, the patients with a defective genotype of Mi R-196a2rs11614913 were more sensitive to chemotherapy. (2) The genotype of the Mi R-196a2rs11614913 genotype was short. (3) Patients with the Mi R-196a2rs11614913 polymorphism can provide a reference for the patient to develop a personalized chemotherapy regimen.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R735.7
【參考文獻】
相關期刊論文 前2條
1 Claudio Napoli;Vincenzo Grimaldi;Maria Rosaria De Pascale;Linda Sommese;Teresa Infante;Andrea Soricelli;;Novel epigenetic-based therapies useful in cardiovascular medicine[J];World Journal of Cardiology;2016年02期
2 Jan AAM Kamps;Guido Krenning;;Micromanaging cardiac regeneration:Targeted delivery of micro RNAs for cardiac repair and regeneration[J];World Journal of Cardiology;2016年02期
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