雌激素受体及相关代谢酶基因单核苷酸多态性与恶性肿瘤发病风险及生存的关联研究

发布时间：2018-04-17 14:54

本文选题：单核苷酸多态性 + 食管癌　；参考：《华中科技大学》2015年博士论文

【摘要】：研究目的：探索雌激素受体及其相关代谢酶基因多态性位点与食管癌发病风险之间的关联。材料和方法：根据文献报道,选择ESR2rs4986938, ESR2rs1256049, CYP1B1rs1056836三个基因多态性位点,采用MGB-Taqman探针法,对473例正常对照和310例经病理证实的食管鳞癌个体进行基因分型。采用多因素非条件性logistic回归分析,经性别、年龄、吸烟、饮酒校正后,观察共显性、显性以及隐性遗传3种遗传模式下,上述基因多态性与食管癌的发病风险之间的关系,以称优势比(odds ratio, OR)及其95%可信区间(95%confidence interval,95%CI)表示相对危险度。结果：结果发现隐性遗传模式下,携带ESR2rs1256049CC/CT基因型的个体较TT基因型的个体患食管鳞癌的风险升高,且该差异具有统计学意义(P=0.002, OR=2.370,95%CI=1.390-4.043)。按照性别进行分层分析发现,在男性人群中,携带ESR2rs1256049CC/CT基因型的个体较TT基因型的个体患食管鳞癌的风险升高,且该差异具有统计学意义(P=0.005, OR=2.396,95%CI=1.303-4.043)。未发现ESR2rs4986938, CYP1B1rs1056836与食管癌发病风险相关结论：ESR2rs1256049CC/CT基因型与食管癌的发病风险具有显著的相关性,其发挥作用的机制有待进一步阐明。研究目的：大肠癌(CRC),是常见的危害人类生命健康的消化道恶性肿瘤。流行病学调查显示男性发病率高于女性,雌激素可能是导致这种性别差异比的原因之一。过去的许多研究发现雌激素受体及其相关代谢酶基因的多态性位点(SNPs)与大肠癌的发病风险相关,然而这些SNPs与大肠癌的生存之间的关系的研究却很少。本研究旨在讨论雌激素受体及其相关代谢酶基因SNPs与大肠癌总体生存的关系。材料和方法：提取355例大肠癌病人的外周血DNA,选择ESR1rs9340799, ESR1rs2234693, ESR2rs4986938, ESR2rs1256049, CYP1BI1s1056836以及CYP17rs743572六个SNP位点,采用MGB-Taqman探针法对上述SNP位点进行基因分型,通过log-rank检验显著性,根据Kaplan-Meier绘制生存曲线。多因素分析采用Cox回归模型,采用性别,年龄,吸烟,肿瘤分期,有无辅助化疗等多因素进行校正结果：经过单因素和多因素生存分析,结果发现6个SNP位点中,大肠癌患者中携带CYPIBI rs1056836CG/GG基因型的个体较CC基因型个体生存差,且差异具有统计学意义(中位生存时间70.6m vs.83.0m, HR=1.628,95%CI=1.039-2.551, P=0.016)。我们按照直肠癌和结肠癌做分层分析后,结果发现在直肠癌亚组分析中,CYP1B1rs1056836与直肠癌的总体生存相关,携带CG/GG基因型的个体较CC基因型的个体总体生存差,且差异具有统计学意义(HR=1.689,95%CI=1.006-2.836,P=0.018)。除此之外,未发现ESR1rs9340799, ESR1rs2234693, ESR2rs4986938, ESR2rs1256049，，以及CYP17rs743572与大肠癌生存之间存在相关性。结论：CYPIBI rs1056836多态性与大肠癌的总体生存相关,可能成为大肠癌生存的预测因素。背景：流行病学调查研究显示肺癌患者患病率之间存在一定的男女性别差异,而临床研究显示女性非小细胞肺癌患者对于生长因子表皮受体-酪氨酸激酶抑制剂(EGFR-TKIs)较男性有较好的效果,这些结果提示雌激素及其合成和代谢相关酶的单核苷酸多态性位点(SNPs)可能与上述差异有关。材料和方法：肺癌发病风险人群：病例组为2008年1月～2010年2月,经病理确诊的肺癌患者,来自于武汉同济医院,共599人。对照组来自于同时期武汉同济医院无肿瘤病史的健康体检人群,共704人。服用EGFR-TKIs的非小细胞肺癌生存人群：来自于2008年1月～2011年12月期间,同济医院服用吉非替尼(Gefitinib)或厄罗替尼(Eroltinib)的非小细胞肺癌患者,共235人。用全血试剂盒(whole blood DNA kit)提取上述人群外周血DNA,-80℃保存。根据公共SNP数据库及相关文献报道,选择雌激素受体及其相关代谢酶基因ESR1,ESR2, CYP1B1以及CYP17的6个SNP位点,采用MGB-Taqman探针法对上述SNP位点进行基因分型。另外,我们利用38例NSCLC术后的石蜡包埋标本,采用免疫组化法检测CYP1B1的表达与基因型的关系。应用SPSS16.0软件,采用多因素非条件性logistic回归分析基因型与肺癌发病风险之间的关系,基因型与生存之间相关性的单因素分析采用Kaplan-Meier生存分析和log-rank法,多因素分析采用Cox回归模型。结果：研究表明携带CYPIBI rs1056836CG/GG基因型较CC基因型的个体其肺癌的发病风险升高,其差异具有统计学意义(OR=1.339,95%CI=1.009-1.778,P=0.043)。同时结果还发现在服用EGFR-TKIs的非小细胞肺癌患者中携带CYPIBI rs1056836CG/GG基因型较CC基因型的患者的生存差,且差异具有统计学意义(中位生存时间13.2m vs.21.0m, HR=1.667,95%CI=1.126-2.468，P=0.011)。另外,对上述两个人群的女性不吸烟患者的亚组分析结果显示,携带CYP1B1rs1056836CG/GG基因型的个体与CC基因型相比,其肺癌发病风险较整体人群更高(OR=1,744),生存时间差异更加显著(中位生存时间28.4m vs.16.5m, HR=1.931). 结论：CYP1B1rs1056836基因多态性与个体罹患肺癌的风险之间存在相关性。另外,CYP1B1rs106836基因多态性还与接受EGFR-TKIs治疗的非小细胞肺癌患者的生存相关。这一结果可以帮助我们预测肺癌的发病风险以及非小细胞肺癌接受EGFR-TKIs治疗后的生存。
[Abstract]:Objective : To explore the association between estrogen receptor and its associated metabolic enzyme gene polymorphism site and risk of esophageal cancer .

Materials and Methods : According to the literature , three genetic polymorphisms of ESR2rs4986938 , ESR2rs1256049 , CYP1Brs1056836 were selected .

Results : The risk of esophageal squamous cell carcinoma of individuals with genotype of ESR2rs1256049CC / CT was increased in the recessive inheritance model , and the difference was statistically significant ( P = 0.002 , OR = 2.370 , 95 % CI = 1.390 - 4.043 ) . According to the stratified analysis of sex , individuals with the ESR2rs1256049CC / CT genotype had increased risk of esophageal squamous cell carcinoma in men , and the difference was statistically significant ( P = 0.005 , OR = 2.396 , 95 % CI = 1.303 - 4.043 ) . It was not found that ESR2rs4986938 , CYP1B2rs1056836 was associated with the risk of esophageal cancer .

Conclusion : ESR2rs1256049CC / CT genotype has a significant correlation with the risk of esophageal cancer , and its mechanism is to be further clarified .

Research purposes : Colorectal cancer ( CRC ) is a common malignant tumor in the digestive tract . The epidemiological investigation shows that the incidence of males is higher than that of females , estrogen may be one of the causes of this sex difference ratio . In the past many studies have found that the polymorphism sites ( SNPs ) of estrogen receptors and their associated metabolic enzymes genes are associated with the risk of colorectal cancer . However , there are few studies on the relationship between these SNPs and the survival of colorectal cancer . The aim of this study is to discuss the relationship between the SNPs of estrogen receptors and their associated metabolic enzymes and the overall survival of colorectal cancer .

Materials and Methods : The peripheral blood DNA of 355 patients with colorectal cancer was extracted , ESR1rs9340799 , ESR1rs2234693 , ESR2rs4986938 , ESR2rs1256049 , CYP1BI1s1056836 , and CYP17rs743572 were genotyped .

Results : Single - factor and multi - factor survival analysis showed that the individuals with CYPIBI rs1056836CG / GG genotype had poor survival in 6 SNP sites , and the difference was statistically significant ( median survival time 70.6m vs . 83.0 m , HR = 1.628 , 95 % CI = 1.039 - 2.551 , P = 0.0016 ) . In addition , ESR1 rs9340799 , ESR1rs2234693 , ESR2rs4986938 , ESR2rs1256049 , and CYP17rs743572 were found to be related to the survival of colorectal cancer .

Conclusion : CYPIBI rs1056836 polymorphism is associated with the overall survival of colorectal cancer , which may be a predictor of colorectal cancer survival .

Background : Epidemiological investigation shows that there is a certain gender difference between the prevalence rates of EGFR - TKIs and EGFR - TKIs . These results suggest that the single nucleotide polymorphism sites ( SNPs ) of estrogen and its synthesis and metabolism - related enzymes may be related to the above differences .

Materials and Methods : The risk population of lung cancer : The case group was from January 2008 to February 2010 . From January 2008 to December 2011 , there were 599 patients with non - small cell lung cancer in Wuhan Tongji Hospital .

Results : The study showed that the risk of lung cancer in individuals carrying CYPIBI rs1056836CG / GG genotype was higher than CC genotype ( OR = 1.339 , 95 % CI = 1.009 - 1.778 , P = 0.043 ) . The results also found that the difference was statistically significant in patients with non - small cell lung cancer taking EGFR - TKIs ( 13.2m vs.21 . 0m , HR = 1.667 , 95 % CI = 1.126 - 2.468 , P = 0 . 011 ) . In addition , the subgroup analysis of female non - smoking patients in the above two populations showed that the risk of lung cancer was higher than that of CC genotype ( OR = 1,744 ) compared with CC genotype . The difference of survival time was more significant ( median survival time : 28.4m vs . 16.5m , HR = 1.931 ) .

Conclusion : There is a correlation between the polymorphism of CYP1B166836 gene and the risk of lung cancer in individuals . In addition , the polymorphism of CYP1B2rs106836 gene is related to the survival of non - small cell lung cancer patients treated with EGFR - TKIs . This results can help us to predict the risk of lung cancer and the survival of non - small cell lung cancer after receiving EGFR - TKIs .

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.1

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