结肠癌胸苷酸合酶基因多态性的研究
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摘要
第一部分胸苷酸合酶蛋白在结肠癌组织中的表达及相关性研究
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)蛋白的表达及其与临床病理因素的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,链霉菌抗生素蛋白—过氧化酶(Streptavidin-Peroxidase,SP)超敏免疫组化检测TS蛋白的表达,并结合相应的临床资料予以分析。
结果：TS蛋白在结肠癌、癌旁组织中的阳性表达率分别为：94%(64/68)、84%(57/68),两者半定量免疫反应评分(immunoreactivity score, IRS)差异有统计学意义(P<0.05)。TS蛋白表达与性别、年龄(>50岁和<50岁)、发病部位、肿瘤长径、组织类型无关(P>0.05)。TS蛋白表达与结肠癌组织的分化程度有关：高分化者TS的IRS均值为2.22,中分化和低分化者分别为4.93和5.41,差异有统计学意义(P=0.026,P<0.05)。TS蛋白的表达在Dukes分期呈递增趋势,A期结肠癌组织中表达明显低于B期和C期,差异有统计学意义(P=0.021,P<0.05)。不同TNM分期的结肠癌组织中,TNMⅢ期结肠癌组织中TS表达高于Ⅰ和Ⅱ期者,差异有统计学意义(P=0.028,P<0.05)。有淋巴结转移的结肠癌组织中TS蛋白表达也高于无淋巴结转移的结肠癌组织,差异有统计学意义(P=0.012,P<0.05)。
结论：TS表达水平的高低与患者的年龄、性别,肿瘤部位无关,而与肿瘤分化程度、浸润深度相关,提示TS在结肠癌的发生和发展进程中起着重要的作用；TS表达与淋巴结转移与否及临床分期有关,提示结肠癌患者的TS表达可能与其预后相关。
第二部分胸苷酸合酶基因多态性与结肠癌临床病理因素的关系
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)基因多态性(gene polymorphism)与其临床病理因素的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,采用多聚酶链式反应(PCR)技术检测68例结肠癌原发灶TS基因多态性,并结合相应的临床资料予以分析。
结果：结肠癌TS基因存在多态性,表现为纯合子2R/2R、3R/3R及两者的杂合子2R/3R。68例中分别为2R/2R基因型6例(8.82%),3R/3R基因型40例(58.82%)和2R/3R基因型22例(32.35%)。68例结肠癌患者中,2R/2R、2R/3R基因型与3R/3R基因型在性别、年龄、肿瘤部位、肿瘤大小、肿瘤大体分型及组织学分级的分布差异无统计学意义(P>0.05)。但在浸润深度、临床分期及淋巴结转移的分布差异有统计学意义(P<0.05)。浸润较深、临床分期晚及出现淋巴结转移的结肠癌组织TS基因型多为3R/3R。基因型为3R/3R的肿瘤组织中TS的IRS与基因型为2R/3R的肿瘤标本TS-IRS,分别为5.73±3.25和3.77±2.64,差异有统计学意义(P=0.015,P<0.05)；基因型为3R/3R的肿瘤组织中TS的IRS明显高于基因型为2R/2R之肿瘤组织(5.73±3.25 vs 2.17±1.47,P=0.008,P<0.05)。2R/3R基因型与2R/2R基因型的肿瘤组织中TS表达差异无统计学意义(P=0.243,P>0.05)。
结论：结肠癌TS基因多态性中存在2R/2R、2R/3R和3R/3R三种基因型,2R/2R、2R/3R与3R/3R基因型在浸润深度、临床分期及淋巴结转移的分布存在差异,3R/3R基因型的结肠癌更容易发生浸润和淋巴结转移。
第三部分结肠癌胸苷酸合酶的表达与肿瘤增殖及凋亡的关系
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)的表达与肿瘤增殖及凋亡的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,SP免疫组化检测增殖细胞核抗原(proliferating cell nuclear antigen, PCNA)的表达,TUNEL法检测凋亡,并结合相应的临床资料予以分析。
结果：68例结肠癌肿瘤患者,TS蛋白表达采用免疫反应评分(immunoreactivity score, IRS)与增殖指数(PI)、凋亡指数(AI)、PI/AI比值均呈正相关(相关系数分别为0.816、0.293、0.426,均P<0.05)。其增殖指数/凋亡指数比值(PI/AI)与患者的性别、年龄、肿瘤部位、肿瘤大体分型、肿瘤分化程度、浸润深度无关(P>0.05)。
结论：结肠癌TS高表达同时伴随PI和AI的增加,只是对PI影响更加显著,导致PI/AI上升。
Part 1. Expression of the thymidylate synthase protein in primary colon cancer and its relationship with clinical pathological parameters
Objective:To investigate the relationship between the expression of thymidylate synthase protein and clinical pathological characteristics of primary colon cancer.
Methods:The expression of thymidylate synthase protein in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues was determined by immunohistochemistry SP method, and its relationship with their corresponding clinical data was analyzed.
Results:The positive expression rate of thymidylate synthase protein in colon cancer and its corresponding paraneoplastic tissues was 94%(64/68)、84%(57/68) respectively, and there was statistically significant difference between the two groups (P<0.05). No correlation was found in expression levels of thymidylate synthase protein with their clinicopathological features such as sex, age, tumor site, tumor long diameter and histological type (P>0.05). The positive expression rate of thymidylate synthase protein in colon cancer of high differentiation degree was less than that in moderate and low differentiation degree (P= 0.026, P<0.05). The positive expression rate of thymidylate synthase protein in colon cancer of Dukes stage A was less than that in Dukes stage B and C (P= 0.021, P<0.05).The positive expression rate of thymidylate synthase protein in colon cancer of TNMⅢwas more than that in TNMⅠandⅡ(P= 0.021, P<0.05).The positive expression rate of thymidylate synthase protein in colon cancer with tumor invasion was higher than that in colon cancer without tumor invasion.
Conclusion:The expression levels of thymidylate synthase protein in colon cancer was not associated with age, sex, tumor site.Thymidylate synthase expression was significantly correlated with histological grading and the depth of tumor invasion. There may be existed the mechanism of coordination in generation and progression of colon cancer. Expression level of thymidylate synthase protein was associated with lymph node metastasis and clinical stage.Thymidylate synthase protein expression is usefull factor related to judge the prognosis in colon cancer.
Part 2. Polymorphisms of the thymidylate synthase gene in primary colon cancer and its relationship with clinical pathological parameters
Objective:To investigate the relationship between polymorphisms in the thymidylate synthase gene and clinical pathological characteristics of primary colon cancer.
Methods:The polymorphism of thymidylate synthase gene in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues was detected by polymerase chain reaction method, and its relationship with their corresponding clinical data was analyzed.
Results:There were three genotypes of thymidylate synthase gene including homozygous with double tandem repeats (2R/2R), homozygous with triple tandem repeats (3R/3R) and heterozygous with both alleles (2R/3R) in 68 cases of colon cancer (6,40,22 cases respectively). No correlation was found between the three genotypes of thymidylate synthase gene with their clinicopathological features such as sex, age, tumor site, tumor long diameter, general type and histological type (P>0.05) 3R/3R type existed more than the other two types with the depth of tumor invasion, clinical stage and lymph node metastasis (P<0.05). IRS (immunoreactivity score) of 3R/3R type was higher than it in 2R/3R type (5.73±3.25,3.77±2.64 respectively, P= 0.015, P<0.05). IRS of 3R/3R type was higher than it in 2R/2R type (5.73±3.25, 2.17±1.47 respectively, P= 0.008, P<0.05). There was no statistically difference of IRS between 2R/3R type and 2R/2R type (P= 0.243, P>0.05)
Conclusion:There were three genotypes of thymidylate synthase gene including homozygous with double tandem repeats (2R/2R), homozygous with triple tandem repeats (3R/3R) and heterozygous with both alleles (2R/3R) in 68 cases of colon cancer(6,40,22 cases respectively). There was statistically difference between 3R/3R and 2R/2R,2R/3R in the depth of tumor invasion, clinical stage and lymph node metastasis. The colon cancer with 3R/3R genotype was liable to tumor invasion and lymph node metastasis.
Part 3. Expression of the thymidylate synthase protein in primary colon cancer and its relationship with malignant proliferation, apoptosis
Objective:To investigate the relationship between expression of the thymidylate synthase protein and malignant proliferation, apoptosis of primary colon cancer.
Methods:Immunohistochemistry SP method was used to determine the expression of proliferating cell nuclear antigen (PCNA) and thymidylate synthase protein, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to detect cell apoptosis in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues. The relationship between immunoreactivity score of thymidylate synthase with proliferative index(PI)and apoptotic index(AI)was analyzed.
Results:No correlation was found between the ratio of proliferative index and apoptosis index with their clinicopathological features such as sex, age, tumor site, tumor long diameter, general type and histological type (P>0.05). There was a positive correlation between immunoreactivity score of thymidylate synthase protein and PI、AI and PI/AI ratio (r=0.816、0.293、0.426, P<0.05)
Conclusion:The colon cancer with high expression of thymidylate synthase protein with higher PI and result in increasing the PI/AI ratio.
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)蛋白的表达及其与临床病理因素的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,链霉菌抗生素蛋白—过氧化酶(Streptavidin-Peroxidase,SP)超敏免疫组化检测TS蛋白的表达,并结合相应的临床资料予以分析。
结果：TS蛋白在结肠癌、癌旁组织中的阳性表达率分别为：94%(64/68)、84%(57/68),两者半定量免疫反应评分(immunoreactivity score, IRS)差异有统计学意义(P<0.05)。TS蛋白表达与性别、年龄(>50岁和<50岁)、发病部位、肿瘤长径、组织类型无关(P>0.05)。TS蛋白表达与结肠癌组织的分化程度有关：高分化者TS的IRS均值为2.22,中分化和低分化者分别为4.93和5.41,差异有统计学意义(P=0.026,P<0.05)。TS蛋白的表达在Dukes分期呈递增趋势,A期结肠癌组织中表达明显低于B期和C期,差异有统计学意义(P=0.021,P<0.05)。不同TNM分期的结肠癌组织中,TNMⅢ期结肠癌组织中TS表达高于Ⅰ和Ⅱ期者,差异有统计学意义(P=0.028,P<0.05)。有淋巴结转移的结肠癌组织中TS蛋白表达也高于无淋巴结转移的结肠癌组织,差异有统计学意义(P=0.012,P<0.05)。
结论：TS表达水平的高低与患者的年龄、性别,肿瘤部位无关,而与肿瘤分化程度、浸润深度相关,提示TS在结肠癌的发生和发展进程中起着重要的作用；TS表达与淋巴结转移与否及临床分期有关,提示结肠癌患者的TS表达可能与其预后相关。
第二部分胸苷酸合酶基因多态性与结肠癌临床病理因素的关系
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)基因多态性(gene polymorphism)与其临床病理因素的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,采用多聚酶链式反应(PCR)技术检测68例结肠癌原发灶TS基因多态性,并结合相应的临床资料予以分析。
结果：结肠癌TS基因存在多态性,表现为纯合子2R/2R、3R/3R及两者的杂合子2R/3R。68例中分别为2R/2R基因型6例(8.82%),3R/3R基因型40例(58.82%)和2R/3R基因型22例(32.35%)。68例结肠癌患者中,2R/2R、2R/3R基因型与3R/3R基因型在性别、年龄、肿瘤部位、肿瘤大小、肿瘤大体分型及组织学分级的分布差异无统计学意义(P>0.05)。但在浸润深度、临床分期及淋巴结转移的分布差异有统计学意义(P<0.05)。浸润较深、临床分期晚及出现淋巴结转移的结肠癌组织TS基因型多为3R/3R。基因型为3R/3R的肿瘤组织中TS的IRS与基因型为2R/3R的肿瘤标本TS-IRS,分别为5.73±3.25和3.77±2.64,差异有统计学意义(P=0.015,P<0.05)；基因型为3R/3R的肿瘤组织中TS的IRS明显高于基因型为2R/2R之肿瘤组织(5.73±3.25 vs 2.17±1.47,P=0.008,P<0.05)。2R/3R基因型与2R/2R基因型的肿瘤组织中TS表达差异无统计学意义(P=0.243,P>0.05)。
结论：结肠癌TS基因多态性中存在2R/2R、2R/3R和3R/3R三种基因型,2R/2R、2R/3R与3R/3R基因型在浸润深度、临床分期及淋巴结转移的分布存在差异,3R/3R基因型的结肠癌更容易发生浸润和淋巴结转移。
第三部分结肠癌胸苷酸合酶的表达与肿瘤增殖及凋亡的关系
目的：探讨结肠癌原发灶中胸苷酸合酶(thymidylate synthase, TS)的表达与肿瘤增殖及凋亡的关系。
方法：收集2002年3月至2005年6月,行手术治疗并经病理证实的结肠癌标本及其相应癌旁组织各68例,SP免疫组化检测增殖细胞核抗原(proliferating cell nuclear antigen, PCNA)的表达,TUNEL法检测凋亡,并结合相应的临床资料予以分析。
结果：68例结肠癌肿瘤患者,TS蛋白表达采用免疫反应评分(immunoreactivity score, IRS)与增殖指数(PI)、凋亡指数(AI)、PI/AI比值均呈正相关(相关系数分别为0.816、0.293、0.426,均P<0.05)。其增殖指数/凋亡指数比值(PI/AI)与患者的性别、年龄、肿瘤部位、肿瘤大体分型、肿瘤分化程度、浸润深度无关(P>0.05)。
结论：结肠癌TS高表达同时伴随PI和AI的增加,只是对PI影响更加显著,导致PI/AI上升。
Part 1. Expression of the thymidylate synthase protein in primary colon cancer and its relationship with clinical pathological parameters
Objective:To investigate the relationship between the expression of thymidylate synthase protein and clinical pathological characteristics of primary colon cancer.
Methods:The expression of thymidylate synthase protein in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues was determined by immunohistochemistry SP method, and its relationship with their corresponding clinical data was analyzed.
Results:The positive expression rate of thymidylate synthase protein in colon cancer and its corresponding paraneoplastic tissues was 94%(64/68)、84%(57/68) respectively, and there was statistically significant difference between the two groups (P<0.05). No correlation was found in expression levels of thymidylate synthase protein with their clinicopathological features such as sex, age, tumor site, tumor long diameter and histological type (P>0.05). The positive expression rate of thymidylate synthase protein in colon cancer of high differentiation degree was less than that in moderate and low differentiation degree (P= 0.026, P<0.05). The positive expression rate of thymidylate synthase protein in colon cancer of Dukes stage A was less than that in Dukes stage B and C (P= 0.021, P<0.05).The positive expression rate of thymidylate synthase protein in colon cancer of TNMⅢwas more than that in TNMⅠandⅡ(P= 0.021, P<0.05).The positive expression rate of thymidylate synthase protein in colon cancer with tumor invasion was higher than that in colon cancer without tumor invasion.
Conclusion:The expression levels of thymidylate synthase protein in colon cancer was not associated with age, sex, tumor site.Thymidylate synthase expression was significantly correlated with histological grading and the depth of tumor invasion. There may be existed the mechanism of coordination in generation and progression of colon cancer. Expression level of thymidylate synthase protein was associated with lymph node metastasis and clinical stage.Thymidylate synthase protein expression is usefull factor related to judge the prognosis in colon cancer.
Part 2. Polymorphisms of the thymidylate synthase gene in primary colon cancer and its relationship with clinical pathological parameters
Objective:To investigate the relationship between polymorphisms in the thymidylate synthase gene and clinical pathological characteristics of primary colon cancer.
Methods:The polymorphism of thymidylate synthase gene in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues was detected by polymerase chain reaction method, and its relationship with their corresponding clinical data was analyzed.
Results:There were three genotypes of thymidylate synthase gene including homozygous with double tandem repeats (2R/2R), homozygous with triple tandem repeats (3R/3R) and heterozygous with both alleles (2R/3R) in 68 cases of colon cancer (6,40,22 cases respectively). No correlation was found between the three genotypes of thymidylate synthase gene with their clinicopathological features such as sex, age, tumor site, tumor long diameter, general type and histological type (P>0.05) 3R/3R type existed more than the other two types with the depth of tumor invasion, clinical stage and lymph node metastasis (P<0.05). IRS (immunoreactivity score) of 3R/3R type was higher than it in 2R/3R type (5.73±3.25,3.77±2.64 respectively, P= 0.015, P<0.05). IRS of 3R/3R type was higher than it in 2R/2R type (5.73±3.25, 2.17±1.47 respectively, P= 0.008, P<0.05). There was no statistically difference of IRS between 2R/3R type and 2R/2R type (P= 0.243, P>0.05)
Conclusion:There were three genotypes of thymidylate synthase gene including homozygous with double tandem repeats (2R/2R), homozygous with triple tandem repeats (3R/3R) and heterozygous with both alleles (2R/3R) in 68 cases of colon cancer(6,40,22 cases respectively). There was statistically difference between 3R/3R and 2R/2R,2R/3R in the depth of tumor invasion, clinical stage and lymph node metastasis. The colon cancer with 3R/3R genotype was liable to tumor invasion and lymph node metastasis.
Part 3. Expression of the thymidylate synthase protein in primary colon cancer and its relationship with malignant proliferation, apoptosis
Objective:To investigate the relationship between expression of the thymidylate synthase protein and malignant proliferation, apoptosis of primary colon cancer.
Methods:Immunohistochemistry SP method was used to determine the expression of proliferating cell nuclear antigen (PCNA) and thymidylate synthase protein, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to detect cell apoptosis in surgically resected specimens of 68 colon carcinoma and its corresponding paraneoplastic tissues. The relationship between immunoreactivity score of thymidylate synthase with proliferative index(PI)and apoptotic index(AI)was analyzed.
Results:No correlation was found between the ratio of proliferative index and apoptosis index with their clinicopathological features such as sex, age, tumor site, tumor long diameter, general type and histological type (P>0.05). There was a positive correlation between immunoreactivity score of thymidylate synthase protein and PI、AI and PI/AI ratio (r=0.816、0.293、0.426, P<0.05)
Conclusion:The colon cancer with high expression of thymidylate synthase protein with higher PI and result in increasing the PI/AI ratio.
引文
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