基于新疆甲状腺癌人群的肿瘤分子标记物研究
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摘要
研究目的:甲状腺疾病是多因素内分泌疾病,发病率高,临床表现为结节性甲状腺肿、桥本氏甲状腺炎、甲状腺瘤(良性)和甲状腺癌(恶性),全球范围内有超过3亿的人口患有甲状腺疾病,严重威胁到人类健康。甲状腺癌是内分泌系统最常见的恶性肿瘤,是我国女性易患的十大恶性肿瘤之一,近30年来发病率显著上升。新疆是我国多民族聚集地区,各大医院临床收治的各民族甲状腺癌患者例数有明显上升趋势,但是关于新疆地区甲状腺疾病,尤其是甲状腺癌的发病情况尚未见详细研究报道。甲状腺癌是由上皮细胞起源的内分泌恶性肿瘤,分为乳头癌、滤泡癌、髓样癌和未分化癌,其中乳头癌占整个甲状腺癌80-90%。临床影像学诊断技术是该肿瘤的主要诊断手段,但是无法对许多症状不明显的肿瘤做出早期诊断,而且难以辨别症状相似的良性和恶性肿瘤,往往导致非恰当性治疗。开展甲状腺癌的分子遗传学、分子生物学和免疫学研究,了解该肿瘤发病的分子机理,寻找肿瘤早期诊断或鉴别良性和恶性肿瘤的分子标记物,是建立甲状腺癌分子诊断标准、有效预防和治疗的重要切入点。因此,在本研究的第一阶段,对近8年入院收治患者信息进行统计分析,从甲状腺患者群体发病趋势、性别、年龄和族别差异角度,明确新疆甲状腺疾病或甲状腺癌的特点。第二阶段,经文献查新,选择腺癌特异性变化或腺癌相关基因,利用新疆甲状腺疾病资源,对候选基因的蛋白质表达水平进行进一步筛选,确定甲状腺癌特异性上、下调表达基因指标,评价其对甲状腺癌病变的标记作用。第三阶段,选择“第二阶段”研究结果中,具有甲状腺癌特异性下调表达或缺失的基因指标,应用Sequenom MassARRAY甲基化DNA定量分析平台,通过甲状腺乳头癌的候选基因启动子区甲基化水平分析,寻找基于基因高甲基化的甲状腺癌特异性分子标记物。方法:1.收集新疆医科大学第一附属医院2002～2009年间收治的甲状腺疾病患者病例资料6071例,包括甲状腺良性病变5865例,甲状腺癌206例。年龄分布1～91岁,男性1707例,女性4364例。汉族4101例,维吾尔族1160例,其他民族810例。用SPSS13.0及Microsoft Excel 2007软件,分析方法采用x~2检验,检验水准α=0.05。2.收集新疆医科大学第一附属医院在2004年～2010年收治的甲状腺疾病患者的石蜡包埋组织标本共195例,其中不同组织类型的甲状腺癌112例,甲状腺腺瘤26例,桥本氏甲状腺炎15例,结节性甲状腺肿10例,正常甲状腺组织32例。选择11种腺癌特异性上或下调表达候选基因CDH1、MGMT、TIMP3、MLH1、ESR1、DAPK1、APC、RARB、CDKN2A、CALCA和MSX1,应用特异性抗体和免疫组织化学S-P法分析每一个基因的蛋白表达水平。3.研究改良的石蜡包埋组织DNA提取方法,从49例甲状腺乳头癌和23例正常组织的石蜡切片中,提取高质量基因组DNA。设计5种候选基因启动子区CpG岛片段特异性PCR引物,应用Sequenom MassARRAY甲基化DNA定量分析平台,对组织DNA进行甲基化水平定量分析。结果:1、2002～2009年间甲状腺疾病的发病率上升趋势非常明显(2002年282和2009年1238例),其中甲状腺癌所占比例很小(3.39%),良性病变占主导地位(96.61%),而良性病变主要是甲状腺机能亢进和甲状腺肿(48%和40%)。甲状腺癌主要是乳头状癌(81%)和滤泡癌(14%)。甲状腺疾病发病的年龄有性别及其年龄差异,男女比例为1/2.56,有统计学差异(P<0.05)。维、汉民族的甲状腺癌发病比例差异很大,但是其总体分布无明显差异。2、(1)免疫组织化学和统计分析显示,从正常到结节性甲状腺肿、桥本氏甲状腺炎、甲状腺瘤和甲状腺癌患者组,CDH1、MLH1、TIMP3和DAPK1等四种基因的蛋白质表达水平(阳性率)明显递减,其组间差异显著(P<0.05);ESR1、MGMT和RARβ等三种基因的蛋白质表达水平变化与此相反,呈明显的上升趋势,其差异也有统计学意义(P<0.05),而APC基因的蛋白表达水平无差异(P>0.05)。(2)从不同甲状腺癌的临床病理参数角度分析,CDH1蛋白质上调表达或ESR1下调表达水平差异与肿瘤预后密切相关;ESR1蛋白表达与不同肿瘤组织类型密切相关即该蛋白在甲状腺乳头癌中高表达,同时ESR1蛋白表达与临床分期密切相关;DAPK1、ESR1、RARβ蛋白表达水平差异与淋巴结转移相关。故CDH1、ESR1、DAPK1和RARβ蛋白表达水平变化可能成为甲状腺癌组织分型、临床分期、淋巴结转移或预后的检测指标,特别是ESR1蛋白表达与甲状腺癌的组织类型、临床分期、淋巴转移和预后指数有关的重要指标。(3)从甲状腺乳头癌角度分析,CDH1、MLH1、TIMP3、DAPK1、ESR1、MGMT和RARβ等7种基因表达水平变化具有甲状腺乳头癌特异性,与正常比较存在明显差异,且具有统计学意义(P<0.05)。此外,CALCA基因在甲状腺乳头癌组织中表达阳性率高,与正常对照组相比有显著差异,而CDKN2A和MSX1基因的表达水平变化无差异。(4)作为肿瘤特异性基因指标,CDH1与MLH1、MLH1与TIMP3、RARβ与ESR1、RARβ与MGMT及CDKN2A与CALCA蛋白表达水平趋势存在不程度相关性(0.4 一基因均较低。ESR1/RARβ/MGMT三者联合检测甲状腺癌的灵敏度、特异度和准确度很高(67.6、77.8、69.2%),是较高组合,而CDH1、MLH1、TIMP3和DAPK1基因的四者组合是较低组合(41.1、20.9、37.8%),但是两两组合分析中也有比较高的组合如TIMP3/CDH1(46.5、25.0、43.2%)、TIMP3/MLH1(44.1、25.0、40.8%),其余组合均为低组合。3、利用改良的石蜡包埋组织DNA提取方法,我们获得了质检合格的高质量基因组DNA。通过甲状腺乳头癌和正常对照DNA的甲基化DNA定量测试(Sequenom MassArray质谱技术)和数据分析,发现只有TIMP3基因启动子区CpG岛片段(目的片段)甲基化水平定量差异显著(P<0.05),而RARB、CALCA、CDH1和MLH等4种基因的目的片段甲基化无统计学差异(P>0.05)。进一步分析CpG位点的单点甲基化水平差异,看出TIMP3基因的目的片段的CpG-7/CpG-8(联合位点)和CpG-9等三个CpG位点甲基化率在肿瘤与正常对照及临床分期之间均有统计学差异(P<0.05或P<0.01)。结论:1.新疆地区甲状腺疾病的发病率呈上升趋势,女性患病率高于男性并且女性甲状腺癌发病年龄早于男性。良性病变是甲状腺疾病的主题,甲状腺癌所占比例极小,甲状腺机能亢进在良性病变居首位,乳头癌是甲状腺癌主题。虽然新疆甲状腺疾病或甲状腺癌患者群体总体分布无明显的年龄或民族差异,但是维、汉两族的甲状腺癌的构成比例差异很大,而且维吾尔族男女比例高于汉族。2.CDH1、MLH1、TIMP3和DAPK1等四种基因的蛋白质表达水平下调或ESR1、MGMT和RARβ等三种基因上调可能是甲状腺癌特异的分子标记物,其中CDH1、MLH1、TIMP3、DAPK1、ESR1、MGMT和RARβ等基因的表达水平变化更具有甲状腺乳头癌特异性。CDH1、ESR1、DAPK1和RARβ蛋白表达水平变化可能成为甲状腺癌预后、组织分型或淋巴结转移的检测指标,特别是其中ESR1蛋白表达与以上所有参数有关,而以上分子标记物中CDH1、MLH1、TIMP3、RARβ、ESR1、MGMT、CDKN2A和CALCA蛋白表达水平趋势存在一定的相关性。以ESR1、RARβ和MGMT三者联合检测甲状腺癌可以大大提高其检测灵敏度、特异度和准确度,TIMP3与CDH1或MLH1的组合也在较大程度上具有联合检测的意义。3.TIMP3基因启动子区CpG岛发生甲基化是甲状腺乳头癌特异的表观遗传学变化,可能是该蛋白质表达下调或表达缺失的重要原因,但是基因启动子去甲基化可能与RARB、CALCA、CDH1和MLH1基因的表达下调或上调无关。
Objective: Thyroid disease is a high incident endocrinal disease caused by diverse factors and represents such clinical manifestations as nodular goiter, Hashimoto’s thyroiditis, thyroid adenoma(benign)and thyroid cancer(malignant), threatening the health and life of more than three hundred million people in the world. Thyroid cancer is one of the most common endocrine malignancies in China, occurred in one of ten malignant cancers of Chinese women, rapidly increased in last three decades. Xinjiang is multi-ethnic region of China,the increasing trend of the number of thyroid cancer patients from various ethnic groups treated in major hospitals has been noticeable, however, the incidence of thyroid disease, specially the thyroid cancer in Xinjiang has not been reported so far.Thyroid cancer is a kind of malignant tumor of epithelial cell origin, generally represents the papillary thyroid cancer, follicular thyroid carcinoma, undifferentiated thyroid carcinoma and medullar thyroid carcinoma, with the ratio of 80-90% for papillary thyroid cancer.Medical imaging is the main method for the diagnoses of the cancer, but often fails in early detection of many tumors without distinct clinical symptoms, and always leads to unsuitable treatment because of difficulties in distinguishing benign and malignant tumors with similar clinical features.To study the thyroid cancer by molecular genetics, molecular biology and immunology, to understand the molecular mechanism of the cancer development, to discover the molecular markers for early diagnosis or discrimination of the begin from malignant tumor, is a cutting edge to establish molecular diagnostic profile, effective prevention and clinical treatment of the cancer.Therefore, in the first part of this study, we will analyze the case information of patients treated in the hospital in last eight years, and understand the development state of thyroid diseases or thyroid cancer in Xinjiang in different aspects such as the morbidity trend, gender, age, and ethnic groups.In the second part, we will search for candidate genes specific or related to adenocarcinoma confirmed in previous reports, screen the up-and down-regulated gene profile in thyroid cancer at protein expression level based on cases treated in Xinjiang, and evaluate the role as biomarkers for thyroid disease development. In the third part, we will focus on genes down-regulated or lost in protein expression according to the data generated from the“second part”, identify molecular markers hypermethylated in, and specific to, papillary thyroid cancer by analysis of candidate gene methylation at promoter region using Sequenom MassARRAY platform for quantitative analysis of methylated DNA. Method:1.We collected the information of 6071 case according to the archive of the first affiliated hospital of Xinjiang medical university from 2002～2009, including 5865 cases of thyroid begin lesions and 206 cases of thyroid cancer, with age range of 1～91, 1707 cases of male, 4364 cases of female, 4191 cases of Han, 1160 cases of Uyghur, 810 cases of other ethnic groups. SPSS13.0 and Microsoft Excel 2007 were used for statistical analysis, x~2 with significance atα=0.05.2.195 formalin fixed and paraffin-embedded thyroid specimens were collected from the period of 2004～2010, in tissue bank of pathology department of first affiliated hospital of Xinjiang medical university, divided into 112 cases of thyroid cancer, 10 cases of nodular goiter, 15 cases of Hashimoto’s thyroiditis, 26 cases of thyroid adenoma, 32 cases of normal tissue. Eleven thyroid cancer-specific up-or down-regulated candidate genes CDH1, MGMT, TIMP3, ESR1, DAPK1, RARB, APC, CDKN2A and MSX1 were selected for the analysis of protein expression level of single gene by immunohistochemical S-P method with specific antibodies. 3.High quality tissue DNA was prepared from 49 papillary thyroid cancer tissue specimens and from 23 normal tissue specimens using the improved genomic DNA extraction method resulted from the pilot experiment. PCR primes specific to CpG Island of promoter region of 5 types of candidate genes were designed for the quantitative analysis of methylation in tissue DNA by Sequenom MassARRAY platform.Result:1.The incidence of the thyroid cancer has markedly increased from 2002～2009,the ratio of thyroid cancer cases was very low (3.39%) compared to benign lesion(s96.61%)representing mainly the Graves' disease and nodular goite(r48 and 4 0%, respectively). Papillary thyroid cancer(81%) and folicular cancer(14%)were the main types of thyroid cancer. The morbidity of thyroid disease has significant difference among various age ranges, and in gender with a male to female ratio of 1/2.56(P <0.05).The ratio of Han and Uyghur ethnic group in all cases was dominant ones, but no difference was found in the distribution of both groups in all disease types.The ratio between female to male significantly higher than the ratio of Han’s both in thyroid disease or in thyroid cancer.2.①Immunohistochemical and statistical analysis showed that the protein express level (positive rate) of CDH1, MLH1, TIMP3 and DAPK1 genes was
significantly decreased from the group of normal tissues to nodular goiter, Hashimoto’s thyroiditis, thyroid adenoma and thyroid cancer(P <0.05), and in contrast, the alteration trend of ESR1, MGMT and RARβprotein expression remarkably increased with statistical significance. But no difference was found for APC.②From the clinicopathological point of view, the downregulation of CDH1 protein expression or the upregulation of ESR1 were closely associated with the prognosis and types of the cancer, whereas the downregulation of DAPK1 or upregulation of RARβcorrelated with lymphnode metastasis(P<0.05).③Analysis focused on the papillary thyroid cancer showed significant difference of CDH1, MLH1, TIMP3, DAPK1, ESR1, MGMT and RARβprotein expression between papillary thyroid cancer and the normal control,(P<0.05).Additionally, the positive rate of CALCA protein expression was significantly higher in papillary thyroid cancer compared to normal control, but no difference was found for CDKN2A and MSX1.④As tumor specific genes of thyroid cancer , CDH1 and MLH1, MLH1 and TIMP3, RARβand ESR1, RARβand MGMT or CDKN2A/p14ARF and CALCA at protein expression level to various exten(t0.4 the promoter region specific to papillary thyroid cancer with statistical difference, in comparison to the normal control (P<0.05),but no difference was shown for RARB, CALCA,CDH1 and MLH1. Further analysis of TIMP3 for single CpG site methylation indicated that the methylation of CpG-7/CpG-8 combination and CpG-9 was quantitatively higher in cancer tissue DNA than in the normal, and associated with the degree of clinical stages(P<0.05 or P<0.01).Conclusion:1. An increasing trend in morbidity was a common feature of thyroid disease in Xinjiang population, high in women patients than in men, earlier age in women patient than in men (malignant)with only a minimal proportion of malignancy compared to the predominance of benign lesions. Papillary thyroid cancer and the Grave’s diseases are the most common types occurred as malignant cancer and benign disease, respectively.Although there was no age or ethnic difference in all thyroid disease types in Xinjiang,whereas there was significant difference at constituent ratio of clinical types of thyroid cancer between the Uyghur and Han,at the same time the ratio of gender of patient in Uyghur higher than in Han.2. (1)The upregulation of CDH1,MLH1,TIMP3 and DAPK1 protein expression or downregulation of ESR1,MGMT and RARβmay be a molecular marker profile of thyroid cancer, and among them, the alteration of CDH1,MLH1, TIMP3,DAPK1,ESR1,MGMT,RARβand CALCA protein level was more specific to papillary thyroid cancer than the other cancer types. (2)The change in CDH1,ESR1,DAPK1and RARβprotein expression may be a important marker for the estimation of prognosis, cancer types or lymphnode metastasis. An association of the alteration trend in protein expression was estimated for CDH1,MLH1,TIMP3,RARβ,ESR1,MGMT,CDKN2A and CALCA. (3)The combined detection with three genes ESR1,RARβand MGMT at protein level may promise a very high sensitivity, specificity and accuracy for the diagnosis of thyroid cancer, whereas the combination of TIMP3with CDH1or MLH1 may also promise a high detection rate of the cancer. 3. The methylation of TIMP3 at promoter region may be an epigenetic event accounting for the downregulation or loss of protein expression specific to papillary thyroid cancer, but not the case for such genes as RARB, CALCA, CDH1 or MLH1.
Objective: Thyroid disease is a high incident endocrinal disease caused by diverse factors and represents such clinical manifestations as nodular goiter, Hashimoto’s thyroiditis, thyroid adenoma(benign)and thyroid cancer(malignant), threatening the health and life of more than three hundred million people in the world. Thyroid cancer is one of the most common endocrine malignancies in China, occurred in one of ten malignant cancers of Chinese women, rapidly increased in last three decades. Xinjiang is multi-ethnic region of China,the increasing trend of the number of thyroid cancer patients from various ethnic groups treated in major hospitals has been noticeable, however, the incidence of thyroid disease, specially the thyroid cancer in Xinjiang has not been reported so far.Thyroid cancer is a kind of malignant tumor of epithelial cell origin, generally represents the papillary thyroid cancer, follicular thyroid carcinoma, undifferentiated thyroid carcinoma and medullar thyroid carcinoma, with the ratio of 80-90% for papillary thyroid cancer.Medical imaging is the main method for the diagnoses of the cancer, but often fails in early detection of many tumors without distinct clinical symptoms, and always leads to unsuitable treatment because of difficulties in distinguishing benign and malignant tumors with similar clinical features.To study the thyroid cancer by molecular genetics, molecular biology and immunology, to understand the molecular mechanism of the cancer development, to discover the molecular markers for early diagnosis or discrimination of the begin from malignant tumor, is a cutting edge to establish molecular diagnostic profile, effective prevention and clinical treatment of the cancer.Therefore, in the first part of this study, we will analyze the case information of patients treated in the hospital in last eight years, and understand the development state of thyroid diseases or thyroid cancer in Xinjiang in different aspects such as the morbidity trend, gender, age, and ethnic groups.In the second part, we will search for candidate genes specific or related to adenocarcinoma confirmed in previous reports, screen the up-and down-regulated gene profile in thyroid cancer at protein expression level based on cases treated in Xinjiang, and evaluate the role as biomarkers for thyroid disease development. In the third part, we will focus on genes down-regulated or lost in protein expression according to the data generated from the“second part”, identify molecular markers hypermethylated in, and specific to, papillary thyroid cancer by analysis of candidate gene methylation at promoter region using Sequenom MassARRAY platform for quantitative analysis of methylated DNA. Method:1.We collected the information of 6071 case according to the archive of the first affiliated hospital of Xinjiang medical university from 2002～2009, including 5865 cases of thyroid begin lesions and 206 cases of thyroid cancer, with age range of 1～91, 1707 cases of male, 4364 cases of female, 4191 cases of Han, 1160 cases of Uyghur, 810 cases of other ethnic groups. SPSS13.0 and Microsoft Excel 2007 were used for statistical analysis, x~2 with significance atα=0.05.2.195 formalin fixed and paraffin-embedded thyroid specimens were collected from the period of 2004～2010, in tissue bank of pathology department of first affiliated hospital of Xinjiang medical university, divided into 112 cases of thyroid cancer, 10 cases of nodular goiter, 15 cases of Hashimoto’s thyroiditis, 26 cases of thyroid adenoma, 32 cases of normal tissue. Eleven thyroid cancer-specific up-or down-regulated candidate genes CDH1, MGMT, TIMP3, ESR1, DAPK1, RARB, APC, CDKN2A and MSX1 were selected for the analysis of protein expression level of single gene by immunohistochemical S-P method with specific antibodies. 3.High quality tissue DNA was prepared from 49 papillary thyroid cancer tissue specimens and from 23 normal tissue specimens using the improved genomic DNA extraction method resulted from the pilot experiment. PCR primes specific to CpG Island of promoter region of 5 types of candidate genes were designed for the quantitative analysis of methylation in tissue DNA by Sequenom MassARRAY platform.Result:1.The incidence of the thyroid cancer has markedly increased from 2002～2009,the ratio of thyroid cancer cases was very low (3.39%) compared to benign lesion(s96.61%)representing mainly the Graves' disease and nodular goite(r48 and 4 0%, respectively). Papillary thyroid cancer(81%) and folicular cancer(14%)were the main types of thyroid cancer. The morbidity of thyroid disease has significant difference among various age ranges, and in gender with a male to female ratio of 1/2.56(P <0.05).The ratio of Han and Uyghur ethnic group in all cases was dominant ones, but no difference was found in the distribution of both groups in all disease types.The ratio between female to male significantly higher than the ratio of Han’s both in thyroid disease or in thyroid cancer.2.①Immunohistochemical and statistical analysis showed that the protein express level (positive rate) of CDH1, MLH1, TIMP3 and DAPK1 genes was
significantly decreased from the group of normal tissues to nodular goiter, Hashimoto’s thyroiditis, thyroid adenoma and thyroid cancer(P <0.05), and in contrast, the alteration trend of ESR1, MGMT and RARβprotein expression remarkably increased with statistical significance. But no difference was found for APC.②From the clinicopathological point of view, the downregulation of CDH1 protein expression or the upregulation of ESR1 were closely associated with the prognosis and types of the cancer, whereas the downregulation of DAPK1 or upregulation of RARβcorrelated with lymphnode metastasis(P<0.05).③Analysis focused on the papillary thyroid cancer showed significant difference of CDH1, MLH1, TIMP3, DAPK1, ESR1, MGMT and RARβprotein expression between papillary thyroid cancer and the normal control,(P<0.05).Additionally, the positive rate of CALCA protein expression was significantly higher in papillary thyroid cancer compared to normal control, but no difference was found for CDKN2A and MSX1.④As tumor specific genes of thyroid cancer , CDH1 and MLH1, MLH1 and TIMP3, RARβand ESR1, RARβand MGMT or CDKN2A/p14ARF and CALCA at protein expression level to various exten(t0.4
引文
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