mTORC1相关基因功能性多态位点与前列腺癌易感性及预后关系的分子流行病学研究
发布时间：2018-07-18 12:25
【摘要】：前列腺癌是男性中最常见的恶性肿瘤之一,其发病具有显著的地区及种族差异。中国前列腺癌的发病率也有逐年升高的趋势。越来越多的证据表明,年龄、种族和家族史是目前公认的与前列腺癌发病相关的三大因素。前列腺癌的发生、发展可能是机体遗传易感性和环境因素相互作用的结果,而与此相关的遗传变异则决定个体罹患前列腺癌的易感性。迄今为止,在世界上不同种族人群中的全基因组关联性研究已经揭示了超过30个易感位点与前列腺癌的发生风险有关。以候选基因为策略的前列腺癌遗传易感性的研究也取得了丰硕的成果。目前认为,前列腺癌的发生、发展及其预后与遗传物质的多态性相关,而且这种相关性随着高危易感基因数目的增加而明显增高。研究还发现,尽管基因多态性与前列腺癌发病风险相关,但这种影响的效应度往往较低,且受环境因素的影响(包括内、外环境)。目前尚无经多中心验证的、较为可靠的与前列腺癌发病风险及预后相关的遗传多态位点。PI3K/AKT/mTOR信号传导通路主要参与蛋白质的合成。近年来,国内外陆续有关该信号转导通路基因单核苷酸多态性与前列腺癌易感性关系的研究报道,但结果不尽一致。研究发现,该信号通路的活性主要与通路下游的哺乳动物雷帕霉素靶蛋白复合物1(mammalian target of rapamycin complex 1, mTORC1)的生物学活性相关,体内体外研究证实mTORC的异常与癌症的发生相关,并且是雷帕霉素作用的靶点。因此,有理由认为该复合物相关基因的多态性位点与前列腺癌发病风险可能相关。mTORC1由一系列直接或间接作用于nTOR的关键分子共同组成,这些分子包括Raptor、mLST8、DEPTOR、PRAS40和]mTOR。其中,Raptor与mLST8起正向调节nTOR的作用,而DEPTOR和PRAS40起负向调节mTOR的作用。本研究将以mTORC1相关基因为候选基因,结合mTOR分子]mRNA及蛋白质的表达及下游靶基因p70S6K和4EBP1的表达,在前列腺癌细胞株和前列腺癌组织标本上进行系统性的研究,有助于发现mTORC1在中国人群中与前列腺癌发病风险有关的遗传易感位点,从而为揭示PI3K/AKT/mTOR信号通路相关基因多态性在前列腺发病中的作用提供可能的遗传学证据,并为前列腺癌术后生化复发的预测提供可能的新的生物学标记。第一部分mTORC1相关基因遗传多态性与前列腺癌易感性的关联性研究为了研究mTORC1相关基因的、具有潜在功能性的SNPs与前列腺癌发病风险的关联性,我们在中国华东地区汉族人群中选择1015例前列腺癌病例和1093例健康男性,开展以医院为基础的病例-对照关联性研究,并采用Taqman探针方法对SNPs进行基因分型检测,运用SAS9.1.3软件包进行统计学描述及关联分析。结果发现,病例组以进展期前列腺癌为主,其中PSA大于20ng/ml的患者占54.4%,小于lOng/ml的患者占17.7%；而Gleason分级≤7(3+4)的患者占31.2%,≥7(3+4)的患者占59.7%；临床分期Ⅰ+Ⅱ期患者占43.3%,Ⅲ+Ⅳ期患者占49.1%。本研究共检测了mTORC1中5个基因的16个SNP位点,结果表明mTOR-rs2536 [加性模型：1.34(1.08-1.66),P=0.008；显性模型：1.42(1.13-1.78),P=0.003],mTOR-rs1034528[加性模型：1.21(1.03-1.42),P=0.019；显性模型：1.29(1.07-1.55), P=0.007], mTOR-rs2295080 [加性模型：0.80(0.69-0.94),P=0.005；显性模型：0.76(0.64-0.92),P=0.003],及RPTOR-rs1062935[加性模型：1.14(1.01-1.29),P=0.0341；显性模型：1.28(1.06-1.56),P=0.0127]与前列腺癌的发病风险显著关联。而亚组分析的结果也表明,mTORC1中mTOR-rs536,-134528,-2295080,以及RPTOR-rs1062935与前列腺癌的发病风险相关,而患前列腺癌的风险也随着复合物中相关风险基因数量的增加而明显提高。本研究中的基因内多位点单倍体分析、基因内多位点联合效应分析、以及基因间的联合效应分析中都发现与前列腺癌发病风险的关联性。在logistic显性模型中我们发现随着风险基因型数目的增加,患前列腺癌的风险也逐渐提高,这种等位基因剂量相关的效应在mTOR多位点的联合分析中显示明显的前列腺癌发病关联性,在小于69岁,BMI体重指数小于24kg/m2,曾经吸烟,Gleason评分≤7(3+4),和临床分期Ⅲ+Ⅳ的人群中尤其明显。在进一步的交互作用分析中,我们发现BMI和mTOR-rs2536 (P=0.0031), BMI和AKTlS1-rs2290774 (P=0.0496),以及DEPTOR-rs4871827与RPTOR-rs1062935 (P=0.0224)之间在前列腺癌发病方面均存在交互作用。综上所述,本研究运用较大的样本量分析了mTORC1中SNPs与前列腺癌发病风险的关连性,并获得了有价值的信息。但是本研究还是存在一些局限性。尚需要多中心、更大样本量及设计更加合理的研究来证实我们的研究结果。第二部分mTOR基因3,非编码区阳性关联位点的功能学研究在第一部分的关联性研究中,我们发现多态位点mTOR-rs2536,-rs1034528,-rs2295080,和RPTOR-rs1062935与前列腺癌的发病风险关联。通过在线SNP分析平台(http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm),我们进一步发现这些位点分别位于相关基因的3'UTR,内含子,基因旁区和内含子区。鉴于3'UTR区是调节基因活性的关键区域,并和肿瘤的发生发展密切关联,因此本部分对mTOR-rs2536的生物学意义进行了功能学研究,探寻其可能的生物学调控机制。在本研究中,我们构建并克隆了含有mTOR 3'UTR全序列的PGL3-Promoter-mTOR3'UTR质粒,质粒中分别导入mTOR-rs2536野生型及突变型碱基。双荧光素报告基因法检测结果显示,瞬时转染miRNA-767-3p类似物48小时后rs2536突变型的荧光相对比值要低于野生型,而该miRNA抑制剂的作用刚好相反,提示miRNA-767-3p对野生型碱基的抑制作用较明显,结果与前期相关性分析结果一致,提示该位点可能通过与相应miRNA结合进而影响mTOR的表达。在随后的SNPexp在线分析平台上做出的基因型-免疫表型相关性分析结果提示,mTOR-rs2536位点影响mTOR基因的表达水平,而且这种影响可能具有种族相关性。在本研究中,我们没有发现mTOR及其下游基因4EBP1和p70S6K的表达与mTOR-rs2536基因型之间的相关性；但我们发现,在癌组织中mTOR的表达水平(35.7%)要高于癌旁组织(28.8%)；而4EBP1在癌组织及癌旁组织中的高表达率分别为32.1%和13.3%；p70S6K在癌组织及癌旁组织中的高表达率分别达到71.4%和39.4%。提示mTOR、4EBP1及p70S6K的活性与前列腺癌的发生或发展相关。综上所述,mTOR-rs2536可能通过影响mTOR 3'UTR与相应miRNA的结合达到调控mTOR的作用。但目前的实验证据还是比较轻微,只能作为一种参考,要证实mTOR3'UTR点突变对mTOR本身表达的实际影响,还需要找到本身带有mTOR该SNP的细胞系进行mRNA和蛋白质水平的研究,才具有确实的说服力。这是本论文的主要不足以及今后研究的方向。第三部分mTORC1相关基因遗传多态位点对前列腺癌临床结局的风险评估在mTORC1相关基因的遗传变异因素与前列腺癌预后的相关性研究中,我们选取423例有较完善临床随访资料的前列腺腺泡腺癌患者,结合前期发病风险关联的易感位点mTOR-rs2536、-rs1034528和-rs2295080以及RPTOR-rs1062935不同基因型进行前列腺癌根治术后的生存预后风险评估。结果发现,在0.1的检验标准下,相对于mTOR-rs1062935TT基因型,携带CT/CC基因型的患者远期生化复发的几率要高(-Plog-rank=0.067);而在该标准下相对于mTOR-rs2536AA基因型,携带GG/AG基因型的患者近期生化复发的几率要高(-PWilcoxon=0.056)。在56例前列腺癌蛋白质表达和预后相关性分析中我们发现,p70s6k的高表达能明显增加前列腺癌术后生化复发的几率,但是本研究中蛋白质表达与随访结果的例数非常有限,结果尚需加大样本量进一步验证。
[Abstract]:Prostate cancer is one of the most common malignant tumors in men, with significant regional and racial differences. The incidence of prostate cancer in China is also increasing year by year. More and more evidence shows that age, race and family history are the three major factors associated with prostate cancer. This may be the result of the interaction of genetic predisposition and environmental factors, and the genetic variation associated with it determines the susceptibility of individuals to prostate cancer. So far, more than 30 susceptible loci in different ethnic groups in the world have been revealed to be associated with the risk of prostate cancer. The study of genetic susceptibility to prostate cancer with candidate genes has also been fruitful. It is now believed that the occurrence, development and prognosis of prostate cancer are associated with genetic polymorphisms, and this correlation increases with the increase in the number of Gao Weiyi genes. The risk of adenocarcinoma is related, but the effect of this effect is often low and is affected by environmental factors (including internal and external environment). There is no multicenter, more reliable genetic polymorphic loci.PI3K/AKT/mTOR signaling pathway related to the risk and prognosis of prostate cancer, which is mainly involved in the synthesis of protein. The study on the relationship between the single nucleotide polymorphism of the signal transduction pathway and the susceptibility to prostate cancer has been reported at home and abroad, but the results are not consistent. The study found that the activity of the signal pathway is mainly with the mammalian rapamycin target protein complex 1 (mammalian target of rapamycin complex 1, mTORC1) downstream. Biological activity is related, in vivo and in vitro studies have confirmed that the abnormality of mTORC is associated with the occurrence of cancer, and is a target for the effect of rapamycin. Therefore, it is reasonable to think that the polymorphic loci of the complex gene may be associated with the risk of prostate cancer and the.MTORC1 is composed of a series of key molecules that direct or indirectly act on nTOR. These molecules include Raptor, mLST8, DEPTOR, PRAS40 and]mTOR., and Raptor and mLST8 play a positive role in regulating nTOR, while DEPTOR and PRAS40 play a negative role in regulating mTOR. Systematic studies on cell lines and prostate cancer specimens help to find mTORC1 genetic susceptibility loci associated with the risk of prostate cancer in Chinese population, thus providing possible genetic evidence to reveal the role of PI3K/AKT/mTOR signaling associated gene polymorphism in the pathogenesis of prostate and for prostate cancer. The prediction of postoperative biochemical recurrence provides possible new biological markers. Part 1 Association of genetic polymorphisms of mTORC1 related genes and prostate cancer susceptibility in order to study the association of mTORC1 related genes with potentially functional SNPs and the risk of prostate cancer. We selected the Han population in eastern China. In 1015 cases of prostate cancer and 1093 healthy men, a case control association study based on the hospital was carried out, and the Taqman probe method was used to detect SNPs genotyping, and the SAS9.1.3 software package was used to carry out statistical description and correlation analysis. The results showed that the case group was mainly the advanced prostate cancer, of which PSA was greater than 20ng/ The patients in ML accounted for 54.4% and less than lOng/ml, while those with Gleason < 7 (3+4) accounted for 31.2% and 7 (3+4) accounted for 59.7%; clinical stage I + II patients accounted for 43.3%, and the patients in stage III + IV accounted for 16 SNP sites of the 5 genes in mTORC1, and the results showed that mTOR-rs2536 [additive model: 1.34 (1.08-1.66) (1.08-1.66). ), P=0.008; explicit model: 1.42 (1.13-1.78), P=0.003], mTOR-rs1034528[additive model: 1.21 (1.03-1.42), P=0.019; dominant model: 1.29 (1.07-1.55), P=0.007], mTOR-rs2295080 [additive model: 0.80 (0.69-0.94), P=0.005; 0.76 (0.64-0.92), 0.76 (0.64-0.92), and additive model: 1.14 0.0341; the dominant model: 1.28 (1.06-1.56), P=0.0127] was associated with the risk of prostate cancer, and the subgroup analysis also showed that mTOR-rs536, -134528, -2295080, and RPTOR-rs1062935 were associated with the risk of prostate cancer, and the risk of prostate cancer also increased with the number of related risk genes in the complex. In this study, the multiple point haploid analysis, intra gene multipoint effect analysis, and the association effect analysis were found to be associated with the risk of prostate cancer. In the logistic dominant model, we found that the risk of prostate cancer is also increased with the increase in the number of risk genotypes. Gradually, the dose dependent effect of this allele was associated with a significant association of prostate cancer in the mTOR multipoint analysis. At the age of less than 69 years, the BMI body mass index was less than 24kg/m2, once smoked, the Gleason score was less than 7 (3+4), and the clinical stage III + IV was especially obvious. In further interaction analysis, we hair BMI and mTOR-rs2536 (P=0.0031), BMI and AKTlS1-rs2290774 (P=0.0496), as well as DEPTOR-rs4871827 and RPTOR-rs1062935 (P=0.0224) have interaction in the pathogenesis of prostate cancer. To sum up, this study used a large sample size to analyze the relationship between SNPs and the risk of prostate cancer in mTORC1 and to obtain the price. However, there are some limitations in this study. We still need multi center, larger sample size and more reasonable design to confirm our research results. Second part of the mTOR gene 3, the functional study of the non coding region positive association loci in the first part of the association study, we found polymorphic loci mTOR-rs2536, -rs 1034528, -rs2295080, and RPTOR-rs1062935 are associated with the risk of prostate cancer. Through the online SNP analysis platform (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm), we further found that these loci are located in the related genes of 3'UTR, intron, para gene and intron. In view of the 3'UTR region is the regulation of gene activity. The key area is closely related to the occurrence and development of the tumor. Therefore, the functional study of the biological significance of mTOR-rs2536 was studied in this part, and the possible mechanism of biological regulation was explored. In this study, we constructed and cloned the PGL3-Promoter-mTOR3'UTR plasmid containing the full sequence of mTOR 3'UTR, and the plasmid was introduced into the wild of mTOR-rs2536 in the wild. The results showed that the relative ratio of the rs2536 mutant was lower than that of the wild type after the transient transfection of miRNA-767-3p analogues for 48 hours, and the effect of the miRNA inhibitor was just the opposite, suggesting that the inhibitory effect of miRNA-767-3p on the wild type base was more obvious, and the results were related to the earlier correlation. The results are consistent, suggesting that the locus may be associated with the corresponding miRNA and then affect the expression of mTOR. The genotype - immunophenotypic correlation analysis made on a subsequent SNPexp online analysis platform suggests that the mTOR-rs2536 locus affects the expression level of the mTOR gene, and this effect may have a racial correlation. In this study, We did not find the correlation between the expression of mTOR and its downstream genes 4EBP1 and p70S6K with the mTOR-rs2536 genotype, but we found that the expression level of mTOR in the cancer tissues (35.7%) was higher than that of the para cancerous tissue (28.8%), and the high expression rate of 4EBP1 in the cancer tissues and Para cancerous tissues was 32.1% and 13.3%, respectively, and p70S6K in cancer tissue and cancer. The high expression rate in the para tissue is 71.4% and 39.4%., respectively, suggesting that the activity of mTOR, 4EBP1 and p70S6K is related to the occurrence or development of prostate cancer. To sum up, mTOR-rs2536 may be used to regulate the role of mTOR 3'UTR and the corresponding miRNA to regulate mTOR. However, the current experimental evidence is still relatively mild and can only be used as a reference. The actual effect of mTOR3'UTR point mutation on the expression of mTOR itself, and the need to find the mRNA and protein levels of the cell lines with mTOR SNP, is a true persuasive. This is the main deficiency of this paper and the direction of future research. The third part of the genetic polymorphic loci of mTORC1 related genes to prostate cancer. The risk assessment of bed outcome was associated with the correlation between the genetic variation factors of mTORC1 related genes and the prognosis of prostate cancer. We selected 423 cases of prostatic adenocarcinoma with more complete clinical follow-up data, the susceptible locus mTOR-rs2536 associated with the preonset risk, -rs1034528 and -rs2295080, and the different bases of RPTOR-rs1062935. The risk assessment of survival after radical prostatectomy was conducted. The results showed that under the 0.1 test standard, the risk of long-term biochemical recurrence was higher in patients carrying CT/CC genotypes than the mTOR-rs1062935TT genotype (-Plog-rank=0.067); compared to the mTOR-rs2536AA genotype, the patients carrying the GG/AG genotype under this standard were in this standard. The risk of recent biochemical recurrence is high (-PWilcoxon=0.056). In the analysis of the protein expression and prognosis of 56 cases of prostate cancer, we found that high expression of P70S6K can significantly increase the risk of postoperative biochemical recurrence of prostate cancer. However, the number of cases of protein expression and follow-up results in this study is very limited, and the results still need to be increased. Further verification.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25
本文编号：2131900
[Abstract]:Prostate cancer is one of the most common malignant tumors in men, with significant regional and racial differences. The incidence of prostate cancer in China is also increasing year by year. More and more evidence shows that age, race and family history are the three major factors associated with prostate cancer. This may be the result of the interaction of genetic predisposition and environmental factors, and the genetic variation associated with it determines the susceptibility of individuals to prostate cancer. So far, more than 30 susceptible loci in different ethnic groups in the world have been revealed to be associated with the risk of prostate cancer. The study of genetic susceptibility to prostate cancer with candidate genes has also been fruitful. It is now believed that the occurrence, development and prognosis of prostate cancer are associated with genetic polymorphisms, and this correlation increases with the increase in the number of Gao Weiyi genes. The risk of adenocarcinoma is related, but the effect of this effect is often low and is affected by environmental factors (including internal and external environment). There is no multicenter, more reliable genetic polymorphic loci.PI3K/AKT/mTOR signaling pathway related to the risk and prognosis of prostate cancer, which is mainly involved in the synthesis of protein. The study on the relationship between the single nucleotide polymorphism of the signal transduction pathway and the susceptibility to prostate cancer has been reported at home and abroad, but the results are not consistent. The study found that the activity of the signal pathway is mainly with the mammalian rapamycin target protein complex 1 (mammalian target of rapamycin complex 1, mTORC1) downstream. Biological activity is related, in vivo and in vitro studies have confirmed that the abnormality of mTORC is associated with the occurrence of cancer, and is a target for the effect of rapamycin. Therefore, it is reasonable to think that the polymorphic loci of the complex gene may be associated with the risk of prostate cancer and the.MTORC1 is composed of a series of key molecules that direct or indirectly act on nTOR. These molecules include Raptor, mLST8, DEPTOR, PRAS40 and]mTOR., and Raptor and mLST8 play a positive role in regulating nTOR, while DEPTOR and PRAS40 play a negative role in regulating mTOR. Systematic studies on cell lines and prostate cancer specimens help to find mTORC1 genetic susceptibility loci associated with the risk of prostate cancer in Chinese population, thus providing possible genetic evidence to reveal the role of PI3K/AKT/mTOR signaling associated gene polymorphism in the pathogenesis of prostate and for prostate cancer. The prediction of postoperative biochemical recurrence provides possible new biological markers. Part 1 Association of genetic polymorphisms of mTORC1 related genes and prostate cancer susceptibility in order to study the association of mTORC1 related genes with potentially functional SNPs and the risk of prostate cancer. We selected the Han population in eastern China. In 1015 cases of prostate cancer and 1093 healthy men, a case control association study based on the hospital was carried out, and the Taqman probe method was used to detect SNPs genotyping, and the SAS9.1.3 software package was used to carry out statistical description and correlation analysis. The results showed that the case group was mainly the advanced prostate cancer, of which PSA was greater than 20ng/ The patients in ML accounted for 54.4% and less than lOng/ml, while those with Gleason < 7 (3+4) accounted for 31.2% and 7 (3+4) accounted for 59.7%; clinical stage I + II patients accounted for 43.3%, and the patients in stage III + IV accounted for 16 SNP sites of the 5 genes in mTORC1, and the results showed that mTOR-rs2536 [additive model: 1.34 (1.08-1.66) (1.08-1.66). ), P=0.008; explicit model: 1.42 (1.13-1.78), P=0.003], mTOR-rs1034528[additive model: 1.21 (1.03-1.42), P=0.019; dominant model: 1.29 (1.07-1.55), P=0.007], mTOR-rs2295080 [additive model: 0.80 (0.69-0.94), P=0.005; 0.76 (0.64-0.92), 0.76 (0.64-0.92), and additive model: 1.14 0.0341; the dominant model: 1.28 (1.06-1.56), P=0.0127] was associated with the risk of prostate cancer, and the subgroup analysis also showed that mTOR-rs536, -134528, -2295080, and RPTOR-rs1062935 were associated with the risk of prostate cancer, and the risk of prostate cancer also increased with the number of related risk genes in the complex. In this study, the multiple point haploid analysis, intra gene multipoint effect analysis, and the association effect analysis were found to be associated with the risk of prostate cancer. In the logistic dominant model, we found that the risk of prostate cancer is also increased with the increase in the number of risk genotypes. Gradually, the dose dependent effect of this allele was associated with a significant association of prostate cancer in the mTOR multipoint analysis. At the age of less than 69 years, the BMI body mass index was less than 24kg/m2, once smoked, the Gleason score was less than 7 (3+4), and the clinical stage III + IV was especially obvious. In further interaction analysis, we hair BMI and mTOR-rs2536 (P=0.0031), BMI and AKTlS1-rs2290774 (P=0.0496), as well as DEPTOR-rs4871827 and RPTOR-rs1062935 (P=0.0224) have interaction in the pathogenesis of prostate cancer. To sum up, this study used a large sample size to analyze the relationship between SNPs and the risk of prostate cancer in mTORC1 and to obtain the price. However, there are some limitations in this study. We still need multi center, larger sample size and more reasonable design to confirm our research results. Second part of the mTOR gene 3, the functional study of the non coding region positive association loci in the first part of the association study, we found polymorphic loci mTOR-rs2536, -rs 1034528, -rs2295080, and RPTOR-rs1062935 are associated with the risk of prostate cancer. Through the online SNP analysis platform (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm), we further found that these loci are located in the related genes of 3'UTR, intron, para gene and intron. In view of the 3'UTR region is the regulation of gene activity. The key area is closely related to the occurrence and development of the tumor. Therefore, the functional study of the biological significance of mTOR-rs2536 was studied in this part, and the possible mechanism of biological regulation was explored. In this study, we constructed and cloned the PGL3-Promoter-mTOR3'UTR plasmid containing the full sequence of mTOR 3'UTR, and the plasmid was introduced into the wild of mTOR-rs2536 in the wild. The results showed that the relative ratio of the rs2536 mutant was lower than that of the wild type after the transient transfection of miRNA-767-3p analogues for 48 hours, and the effect of the miRNA inhibitor was just the opposite, suggesting that the inhibitory effect of miRNA-767-3p on the wild type base was more obvious, and the results were related to the earlier correlation. The results are consistent, suggesting that the locus may be associated with the corresponding miRNA and then affect the expression of mTOR. The genotype - immunophenotypic correlation analysis made on a subsequent SNPexp online analysis platform suggests that the mTOR-rs2536 locus affects the expression level of the mTOR gene, and this effect may have a racial correlation. In this study, We did not find the correlation between the expression of mTOR and its downstream genes 4EBP1 and p70S6K with the mTOR-rs2536 genotype, but we found that the expression level of mTOR in the cancer tissues (35.7%) was higher than that of the para cancerous tissue (28.8%), and the high expression rate of 4EBP1 in the cancer tissues and Para cancerous tissues was 32.1% and 13.3%, respectively, and p70S6K in cancer tissue and cancer. The high expression rate in the para tissue is 71.4% and 39.4%., respectively, suggesting that the activity of mTOR, 4EBP1 and p70S6K is related to the occurrence or development of prostate cancer. To sum up, mTOR-rs2536 may be used to regulate the role of mTOR 3'UTR and the corresponding miRNA to regulate mTOR. However, the current experimental evidence is still relatively mild and can only be used as a reference. The actual effect of mTOR3'UTR point mutation on the expression of mTOR itself, and the need to find the mRNA and protein levels of the cell lines with mTOR SNP, is a true persuasive. This is the main deficiency of this paper and the direction of future research. The third part of the genetic polymorphic loci of mTORC1 related genes to prostate cancer. The risk assessment of bed outcome was associated with the correlation between the genetic variation factors of mTORC1 related genes and the prognosis of prostate cancer. We selected 423 cases of prostatic adenocarcinoma with more complete clinical follow-up data, the susceptible locus mTOR-rs2536 associated with the preonset risk, -rs1034528 and -rs2295080, and the different bases of RPTOR-rs1062935. The risk assessment of survival after radical prostatectomy was conducted. The results showed that under the 0.1 test standard, the risk of long-term biochemical recurrence was higher in patients carrying CT/CC genotypes than the mTOR-rs1062935TT genotype (-Plog-rank=0.067); compared to the mTOR-rs2536AA genotype, the patients carrying the GG/AG genotype under this standard were in this standard. The risk of recent biochemical recurrence is high (-PWilcoxon=0.056). In the analysis of the protein expression and prognosis of 56 cases of prostate cancer, we found that high expression of P70S6K can significantly increase the risk of postoperative biochemical recurrence of prostate cancer. However, the number of cases of protein expression and follow-up results in this study is very limited, and the results still need to be increased. Further verification.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25
【参考文献】
相关期刊论文 前1条
1 祁慧薇;范理宏;;PI3K/Akt/mTOR信号转导通路与非小细胞肺癌[J];中国肺癌杂志;2010年12期
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