乳腺癌微卫星不稳定性和DNA错配修复基因突变的研究
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摘要
研究目的:乳腺癌是女性最常见的恶性肿瘤之一,它是乳腺上皮细胞在多种致癌因素的作用下,发生了基因突变,导致细胞增生失控,呈现出无序、无限制的恶性增生。乳腺癌和其他许多肿瘤一样,是一种多基因参与,多种遗传学改变累积的结果。而细胞的基因组不稳定是导致乳腺癌发生的重要遗传学改变。目前研究认为,人类肿瘤的基因组不稳定性分为两种不同的类型:一种是微卫星不稳定性(microsatellite instability,MSI),另一种是杂合性缺失(Loss of heterozygosity,LOH)。MSI的发生与错配修复基因(mismatch repair gene,MMR)关系密切,MMR基因的表型改变,尤其是两个关键基因hMSH2和hMLH1的突变可能导致基因组不稳定而产生MSI,从而促进肿瘤的发生与发展。本试验通过研究乳腺癌中微卫星不稳定性和DNA错配修复基因hMSH2的突变情况,从hMSH2外显子突变致错配修复功能缺失影响细胞遗传稳定稳定性的角度探讨乳腺癌中MSI发生的可能机制,寻找更有效的分子标志,为乳腺癌的发生及预后评估提供理论依据。
研究方法:收集广西区肿瘤医院2004年至2008年的18例远离癌组织的乳腺组织,39例乳腺良性肿瘤组织和78例乳腺癌组织,用免疫组化方法测定所有标本hMSH2蛋白的表达情况。每例标本用DNA提取试剂盒提取DNA,针对hMSH2基因的16个外显子的碱基序列特征,有目的地设计有助于筛查基因碱基突变的PCR引物,每一例标本的DNA用PCR扩增hMSH2基因的16个外显子。分别将每一例外显子的PCR产物进行SSCP分析,对泳动变位或出现异常区带的PCR扩增产物进行DNA测序。参考文献选取D2S443、D11S988、D21S1436、D3S1766、D2S2739这5个微卫星位点,在基因库中查出相应的引物序列,用PCR扩增后用12%聚丙烯酰胺凝胶电泳,银染显色后进行分析。所有数据均使用SPSS13.0软件进行统计学分析,分类资料采用卡方检验,等级资料采用秩和检验,多变量数据采用Logistic回归分析。所有P值使用双侧检验。
研究结果:①18例远离癌组织的乳腺组织hMSH2的阳性表达率为94.44%(17/18),39例乳腺良性肿物的hMSH2阳性表达率为76.92%(30/39),78例乳腺癌的hMSH2阳性表达率为39.74%(31/78),三组比较差别均有统计学意义(x~2=29.383,p=0.000)。乳腺癌中hMSH2的表达率明显减少。②Lgostici回归分析发现hMSH2的表达与乳腺癌临床因素中的肿物大小、腋窝淋巴结转移及临床分期有关。在肿物较大、有腋窝淋巴结转移及临床分期较晚的乳腺癌病例中更容易观察到hMSH的表达减少。③18例远离癌组织的乳腺组织未见hMSH2基因的突变,39例乳腺良性肿物组织中有1例检测出hMSH2基因的第7外显子突变(409C→G),78例乳腺癌组织中有9例检测出hMSH2基因的突变,分别是外显子6(322G→A,2例)、外显子7(378A→T)、外显子12(623C→G)、外显子12(631A→G,同义突变)、外显子13(727T→G)、外显子14(796A→C,2例同义突变)、外显子14(801A→G)。总突变率为11.54%(9/78),三组比较差别均有统计学意义(x~2=4.332,p=0.037)。在乳腺癌组织中更容易观察到hMSH2的突变。④18例远离癌组织的乳腺组织未见MSI发生,39例乳腺良性肿物组织中有5例至少1个位点发生MSI,MSI的发生率为12.82%(5/39)。78例乳腺癌中有35例至少1个位点出现MSI,MSI的发生率为44.87%(35/78),三组比较差别均有统计学意义(x~2=20.365,p=0.000),乳腺癌组织中更容易发生MSI。⑤Lgostici回归分析发现MSI与乳腺癌hMSH2的表达和临床因素中的临床分期、腋窝淋巴结转移有关。在临床分期晚及有腋窝淋巴结转移的病例更多的发现MSI。⑥关联分析发现hMSH2突变与蛋白表达减少有关(x~2=6.624,p=0.01),与MSI的发生有关(x~2=10.572,p=0.01)。hMSH2蛋白表达与MSI发生有关(x~2=7.463,p=0.006)。9例hMSH2突变的病例均有hMSH2蛋白的表达缺失及MSI的发生。
研究结论:①hMSH2在远离癌的乳腺组织中高表达,在乳腺良性肿物中表达下降,而在乳腺癌中表达率更低。hMSH2的表达缺失与乳腺癌的肿物较大、腋窝淋巴结转移及临床分期晚有关,提示hMSH2蛋白有可能作为乳腺癌判断预后的一个分子标志。②hMSH2基因在乳腺癌中无明显突变热点,突变分散于第6,7,12,13,14外显子,总突变率为11.54%。③乳腺癌中普遍存在着MSI,并与乳腺癌的临床分期和腋窝淋巴结转移有关,提示MSI可能作为判断乳腺癌临床分期的一个分子标志,可能对推测预后提供帮助。④hMSH2基因的突变导致有功能的hMSH2蛋白缺失,进而有可能影响MMR系统的功能,从而可能导致产生微卫星DNA的不稳定性,提示hMSH2在MMR系统中的起着重要作用,与乳腺癌的MSI发生关系密切。
Objective:Breast cancer is the common malignant tumor of women.The gene of mammary gland cellula epithelialis became mutate for the multitude carcinogenic agents,it induce to the cellular proliferation loss of control and make breast cancer happened.The pathogenesis of breast cancer is a process of multiple factors,multiple genes and a series of steps.But the hereditary instability is the most important genetics effect of the pathogenesis of breast cancer,the hereditary instability have two different types:one is microsatellite instability(MSI) and the other one is loss of heterozygosity(LOH).The mutation of mismatch repair genes(MMR),especially the tow important hMSH2 and hMLH1 have closs relationship wite MSI,it will lend to the deficiency of mismatch repair genes result in hereditary instability and cause the MSI happened.Studying breast cancer abnormal changes at molecular and gene level, Which have become the key point to improve the early diagnosis and accurate predict prognosis of breast cancer.In our study in order to explore the mechanism of MSI and mutations of hMSH2 in breast cancer,we detecting the protein expression of DNA mismatch repair hMSH2,the mutation of its exon and the state of MSI in breast cancer.Trying to find a more effective genetic marker, which will make reasonable foundation for research in the cause of breast cancer and prognosis predict of breast cancer.
Methods:78 sample of breast cancers、39 sample of benign tumor of breast and 18 sample of breast tissues away from cancer as control were studied. All samples were obtained from the Affiliated Tumour Hospital of Guangxi Medical University between 2004 and 2008.The protein expression of hMSH2 were detected by immuneohistochemistry S-P method.DNA extracted by DNA extracted kit.The primer sequences of hMSH2 exon were design using the oligo 6 software.Fragments of all exons were amplified by plymerase chain reaction(PCR),and then hMSH2 exons mutations were detected by single-strand conformation polymorphism analysis(PCR-SSCP).Sequencing the DNA which the results of SSCP were abnomal.The five microsatellite situs were choosed according to the literature and findout their sequences in gene bank.The MSI were analyzed by PCR-single strand length polymorphism(SSLP).Results were statistically analyzed by SPSS13.0 software.Categorical data using chi-square test(χ2 test),ordinal data using rank sum test,multivariate analysis using logistic regression.A p value less than 0.05 was considered significant.
Result①Immunohistochemistry results show that hMSH2 expression rate in 18 breast tissues away from cancer、39 breast benign tumor tissues and 78 breast cancer tissues is 94.44%,76.92%and 39.74%respectively.There were statistical difference in these three group(χ2=29.383,p=0.000).The expression of hMSH2 in breast cancer tissues is decrease obviously.②The significant correlation is observed between the decrease rate of hMSH2 protein expression and tumour sise、clinical stage and axillary nodes metabasis.The decrease rate of hMSH2 protein expression is more easily observed in the tissues with big tumour sise、later clinical stage and have axillary nodes metabasis.③It was no hMSH2 gene mutation in the breast tissues away from cancer.1 mutation in exon 7(409C→G) was found in these 39 breast benign tumor tissues.There totally 9 mutation in breast cancer tissues,including 2 mutation in exon 6 (322G→A)、1 mutation in exon 7(378A→T)、1 mutation in exon 12(623C→G)、1 samesense mutation in exon 12(631A→G)、1 mutation in exon 13(727T→G)、2 samesense mutation in exon 14(796A→C) and 1 mutation in exonl4(801A→G).The rate of mutation in breast cancer tissues is 11.54%. There were statistical difference in these three group(χ2=4.332, p=0.037).hMSH2 mutation was more easily observed in the breast cancer tissues.④MSI isn't presented in breast tissues away from cancer,5 of 39 breast benign tumor tissues can found MSI in at least one microsatellite situs,the rate of MSI is 12.82%.35 of 78 breast cancer tissues can found MSI in at least one microsatellite situs,the rate of MSI is 44.87%.There were statistical difference in these three group(χ2=20.365,p＜0.05),MSI was more easily observed in the breast cancer tissues.⑤The significant correlation is observed between the MSI and these tumour sise、clinical stage and axillary nodes metabasis of the breast cancer.The MSI is more easily observed in the tissues with later clinical stage and have axillary nodes metabasis.⑥The hMSH2 mutation is significant correlation with decrease of hMSH2 protein expression (χ2=6.624,p=0.01) and MSI(χ2=10.572,p=0.01).In breast cancer,all hMSH2 mutaton samples can observed the decrease of hMSH2 protein expression and MSI.
Conclusion①hMSH2 protein is high expression in breast tissues away from cancer.hMSH2 protein expression is decrease in breast benign tumor tissues,in breast cancer tissues it decrease the most obviously.②The decrease rate of hMSH2 protein expression is more easily observed in the breast cancer tissues with big tumour sise,later clinical stage and have axillary nodes metabasis,indicate that hMSH2 canbe a genetic marker for predicted prognostic of breast cancer.③hMSH2 have no mutational hot spot in breast cancer, mutation of hMSH2 is distribute in exon 6,7,12,13 and 14.In breast cancer hMSH2 mutation may be a mechanism of the disfunction of MMR system.④MSI is widespread in breast cancer,it is more easily observed in the tissues with later clinical stage and have axillary nodes metabasis,indicate that MSI canbe a genetic marker for clinical stage of breast cancer,it helps to predicted prognostic of breast cancer.Patient with MSI maybe poor prognostic.
研究方法:收集广西区肿瘤医院2004年至2008年的18例远离癌组织的乳腺组织,39例乳腺良性肿瘤组织和78例乳腺癌组织,用免疫组化方法测定所有标本hMSH2蛋白的表达情况。每例标本用DNA提取试剂盒提取DNA,针对hMSH2基因的16个外显子的碱基序列特征,有目的地设计有助于筛查基因碱基突变的PCR引物,每一例标本的DNA用PCR扩增hMSH2基因的16个外显子。分别将每一例外显子的PCR产物进行SSCP分析,对泳动变位或出现异常区带的PCR扩增产物进行DNA测序。参考文献选取D2S443、D11S988、D21S1436、D3S1766、D2S2739这5个微卫星位点,在基因库中查出相应的引物序列,用PCR扩增后用12%聚丙烯酰胺凝胶电泳,银染显色后进行分析。所有数据均使用SPSS13.0软件进行统计学分析,分类资料采用卡方检验,等级资料采用秩和检验,多变量数据采用Logistic回归分析。所有P值使用双侧检验。
研究结果:①18例远离癌组织的乳腺组织hMSH2的阳性表达率为94.44%(17/18),39例乳腺良性肿物的hMSH2阳性表达率为76.92%(30/39),78例乳腺癌的hMSH2阳性表达率为39.74%(31/78),三组比较差别均有统计学意义(x~2=29.383,p=0.000)。乳腺癌中hMSH2的表达率明显减少。②Lgostici回归分析发现hMSH2的表达与乳腺癌临床因素中的肿物大小、腋窝淋巴结转移及临床分期有关。在肿物较大、有腋窝淋巴结转移及临床分期较晚的乳腺癌病例中更容易观察到hMSH的表达减少。③18例远离癌组织的乳腺组织未见hMSH2基因的突变,39例乳腺良性肿物组织中有1例检测出hMSH2基因的第7外显子突变(409C→G),78例乳腺癌组织中有9例检测出hMSH2基因的突变,分别是外显子6(322G→A,2例)、外显子7(378A→T)、外显子12(623C→G)、外显子12(631A→G,同义突变)、外显子13(727T→G)、外显子14(796A→C,2例同义突变)、外显子14(801A→G)。总突变率为11.54%(9/78),三组比较差别均有统计学意义(x~2=4.332,p=0.037)。在乳腺癌组织中更容易观察到hMSH2的突变。④18例远离癌组织的乳腺组织未见MSI发生,39例乳腺良性肿物组织中有5例至少1个位点发生MSI,MSI的发生率为12.82%(5/39)。78例乳腺癌中有35例至少1个位点出现MSI,MSI的发生率为44.87%(35/78),三组比较差别均有统计学意义(x~2=20.365,p=0.000),乳腺癌组织中更容易发生MSI。⑤Lgostici回归分析发现MSI与乳腺癌hMSH2的表达和临床因素中的临床分期、腋窝淋巴结转移有关。在临床分期晚及有腋窝淋巴结转移的病例更多的发现MSI。⑥关联分析发现hMSH2突变与蛋白表达减少有关(x~2=6.624,p=0.01),与MSI的发生有关(x~2=10.572,p=0.01)。hMSH2蛋白表达与MSI发生有关(x~2=7.463,p=0.006)。9例hMSH2突变的病例均有hMSH2蛋白的表达缺失及MSI的发生。
研究结论:①hMSH2在远离癌的乳腺组织中高表达,在乳腺良性肿物中表达下降,而在乳腺癌中表达率更低。hMSH2的表达缺失与乳腺癌的肿物较大、腋窝淋巴结转移及临床分期晚有关,提示hMSH2蛋白有可能作为乳腺癌判断预后的一个分子标志。②hMSH2基因在乳腺癌中无明显突变热点,突变分散于第6,7,12,13,14外显子,总突变率为11.54%。③乳腺癌中普遍存在着MSI,并与乳腺癌的临床分期和腋窝淋巴结转移有关,提示MSI可能作为判断乳腺癌临床分期的一个分子标志,可能对推测预后提供帮助。④hMSH2基因的突变导致有功能的hMSH2蛋白缺失,进而有可能影响MMR系统的功能,从而可能导致产生微卫星DNA的不稳定性,提示hMSH2在MMR系统中的起着重要作用,与乳腺癌的MSI发生关系密切。
Objective:Breast cancer is the common malignant tumor of women.The gene of mammary gland cellula epithelialis became mutate for the multitude carcinogenic agents,it induce to the cellular proliferation loss of control and make breast cancer happened.The pathogenesis of breast cancer is a process of multiple factors,multiple genes and a series of steps.But the hereditary instability is the most important genetics effect of the pathogenesis of breast cancer,the hereditary instability have two different types:one is microsatellite instability(MSI) and the other one is loss of heterozygosity(LOH).The mutation of mismatch repair genes(MMR),especially the tow important hMSH2 and hMLH1 have closs relationship wite MSI,it will lend to the deficiency of mismatch repair genes result in hereditary instability and cause the MSI happened.Studying breast cancer abnormal changes at molecular and gene level, Which have become the key point to improve the early diagnosis and accurate predict prognosis of breast cancer.In our study in order to explore the mechanism of MSI and mutations of hMSH2 in breast cancer,we detecting the protein expression of DNA mismatch repair hMSH2,the mutation of its exon and the state of MSI in breast cancer.Trying to find a more effective genetic marker, which will make reasonable foundation for research in the cause of breast cancer and prognosis predict of breast cancer.
Methods:78 sample of breast cancers、39 sample of benign tumor of breast and 18 sample of breast tissues away from cancer as control were studied. All samples were obtained from the Affiliated Tumour Hospital of Guangxi Medical University between 2004 and 2008.The protein expression of hMSH2 were detected by immuneohistochemistry S-P method.DNA extracted by DNA extracted kit.The primer sequences of hMSH2 exon were design using the oligo 6 software.Fragments of all exons were amplified by plymerase chain reaction(PCR),and then hMSH2 exons mutations were detected by single-strand conformation polymorphism analysis(PCR-SSCP).Sequencing the DNA which the results of SSCP were abnomal.The five microsatellite situs were choosed according to the literature and findout their sequences in gene bank.The MSI were analyzed by PCR-single strand length polymorphism(SSLP).Results were statistically analyzed by SPSS13.0 software.Categorical data using chi-square test(χ2 test),ordinal data using rank sum test,multivariate analysis using logistic regression.A p value less than 0.05 was considered significant.
Result①Immunohistochemistry results show that hMSH2 expression rate in 18 breast tissues away from cancer、39 breast benign tumor tissues and 78 breast cancer tissues is 94.44%,76.92%and 39.74%respectively.There were statistical difference in these three group(χ2=29.383,p=0.000).The expression of hMSH2 in breast cancer tissues is decrease obviously.②The significant correlation is observed between the decrease rate of hMSH2 protein expression and tumour sise、clinical stage and axillary nodes metabasis.The decrease rate of hMSH2 protein expression is more easily observed in the tissues with big tumour sise、later clinical stage and have axillary nodes metabasis.③It was no hMSH2 gene mutation in the breast tissues away from cancer.1 mutation in exon 7(409C→G) was found in these 39 breast benign tumor tissues.There totally 9 mutation in breast cancer tissues,including 2 mutation in exon 6 (322G→A)、1 mutation in exon 7(378A→T)、1 mutation in exon 12(623C→G)、1 samesense mutation in exon 12(631A→G)、1 mutation in exon 13(727T→G)、2 samesense mutation in exon 14(796A→C) and 1 mutation in exonl4(801A→G).The rate of mutation in breast cancer tissues is 11.54%. There were statistical difference in these three group(χ2=4.332, p=0.037).hMSH2 mutation was more easily observed in the breast cancer tissues.④MSI isn't presented in breast tissues away from cancer,5 of 39 breast benign tumor tissues can found MSI in at least one microsatellite situs,the rate of MSI is 12.82%.35 of 78 breast cancer tissues can found MSI in at least one microsatellite situs,the rate of MSI is 44.87%.There were statistical difference in these three group(χ2=20.365,p＜0.05),MSI was more easily observed in the breast cancer tissues.⑤The significant correlation is observed between the MSI and these tumour sise、clinical stage and axillary nodes metabasis of the breast cancer.The MSI is more easily observed in the tissues with later clinical stage and have axillary nodes metabasis.⑥The hMSH2 mutation is significant correlation with decrease of hMSH2 protein expression (χ2=6.624,p=0.01) and MSI(χ2=10.572,p=0.01).In breast cancer,all hMSH2 mutaton samples can observed the decrease of hMSH2 protein expression and MSI.
Conclusion①hMSH2 protein is high expression in breast tissues away from cancer.hMSH2 protein expression is decrease in breast benign tumor tissues,in breast cancer tissues it decrease the most obviously.②The decrease rate of hMSH2 protein expression is more easily observed in the breast cancer tissues with big tumour sise,later clinical stage and have axillary nodes metabasis,indicate that hMSH2 canbe a genetic marker for predicted prognostic of breast cancer.③hMSH2 have no mutational hot spot in breast cancer, mutation of hMSH2 is distribute in exon 6,7,12,13 and 14.In breast cancer hMSH2 mutation may be a mechanism of the disfunction of MMR system.④MSI is widespread in breast cancer,it is more easily observed in the tissues with later clinical stage and have axillary nodes metabasis,indicate that MSI canbe a genetic marker for clinical stage of breast cancer,it helps to predicted prognostic of breast cancer.Patient with MSI maybe poor prognostic.
引文
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