血清microRNA（miRNA）作为胰腺癌诊断和预后生物标志物的研究
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摘要
目前,全球胰腺癌新发病例多达23万/年。平均中位生存时间仅有4到6个月,已成为威胁我国人民生命健康的一大杀手。胰腺癌病人的5年生存率从早期病人的超过50%,迅速下降到进展期病人的不足5%。虽然手术切除是较为有效的胰腺癌治疗手段,但是一直以来由于缺乏良好的诊断标志物,胰腺癌的诊断困难,尤其是早期胰腺癌的诊断缺乏特异的诊断标志物一直是该疾病生存期短、预后不良的主要原因之一。目前临床采用的影像学及一些标志物如CEA,CA19-9等的敏感性和特异性都不够高。另外,胰液的分子标志物、胰腺管刷检、组织穿刺等方法也在临床中有所应用,但是这些方法操作复杂,标本取材困难,临床应用存在一定难度。对于胰腺癌病人如能早期诊断,早期手术切除将大大改善病人的预后与生存。本研究的目的主要是鉴定胰腺癌特异的血清(?)niRNA表达谱,验证其作为胰腺癌诊断标志物的特异性与敏感性,并观察其与胰腺癌病人生存及预后之间的关系。
miRNA (microRNA)是一类长约19-23个核苷酸的小分子单链RNA,它由一段具有发夹结构的单链RNA前体经Drosha酶和Dicer酶的剪切后生成。miRNA通过与目标(?)nRNA分子的3’端非编码区域(3’-UTR)互补配对,使目标mRNA分子的翻译受到抑制或引起特异性的对(?)nRNA分子的切割,从而在转录后水平对靶基因的表达进行调控。大量研究成果表明,miRNA参与着生物体中很多基本生命过程的调控,在生命活动中起着非常重要的作用,miRNA分子不仅自身作为功能分子发挥作用,还广泛参与和决定基因表达调控和蛋白质翻译,进而影响细胞的新陈代谢等所有生命过程。miRNA标志物将成为疾病发生发展相关基因标志物、蛋白质标志物和代谢物标志物整体“网络”中的“结点”。虽然肿瘤组织中的miRNA可以作为一种新的肿瘤标志物,但是,为了获得肿瘤组织(?)miRNA,势必需要进行有创的手术或者穿刺等,所以组织miRNA仍然不能满足早期诊断的需要,仍然不能适用于广泛的筛查和预防。基于此,研究人员将目光投向较易获得,甚至常规体检中就可以收集到的血液。血清的检测是无创的、非侵入的,因此可以适用于普查和预防,为早期诊断服务。随着miRNA研究的不断深入,发现血清、血浆及其它体液中存在miRNA,并发现这些体液来源的miRNA能非侵入地诊断肿瘤等疾病及判断预后。
本研究收集了157份胰腺癌及138份年龄性别相匹配的正常对照。初步采用单分子微阵列(solexa)高通量小分子测序对两组病人的混合血清进行筛选,得出差异表达的血清miRNA,随后通过定量PCR (qRT-PCR)对初筛阶段差异表达的血清miRNA进行大规模、单样本、二阶段的精确定量验证。通过聚类分析、风险评分分析、曲线下面积分析评估该组血清miRNA表达谱对胰腺癌诊断的准确性及可靠性。另选取82例慢性胰腺炎作为第二对照,进一步验证该组标志物对胰腺癌病人和其高危人群慢性胰腺炎的区分能力。进一步选取69例样本(胰腺癌+正常对照)进行双盲实验验证,操作者与结果分析者均不知晓样本信息前提下进行实验及分析验证其诊断的准确性。另选取55例临床疑似胰腺癌的病例进行前瞻性分析,结合后续该55例样本的临床病理诊断来评价该组血清miRNA作为胰腺癌诊断生物标志物的准确性。
通过初步高通量的Solexa测序筛选及qRT-PCR验证过程,得到7个在胰腺癌与正常对照样本间稳定差异表达的miRNA,即：(?)niR-20a, miR-21, miR-24, miR-25, miR-99a, miR-185,及miR-191。采用风险系数评分标准进一步评价7个miRNA表达系统对胰腺癌的诊断能力。该组血清miRNA作为标志物能够将各种阶段的胰腺癌与正常对照样本以较高的敏感性和特异性区分开来,而且,同样能够准确的区分胰腺癌与慢性胰腺炎病例,表明该组标志物是胰腺癌的特异性标志物。进一步构建受试者工作特征曲线(ROC),先采用风险评分方法分别评估所有样本的7个血清miRNA的敏感性及特异性,由此构建ROC,对于第一验证阶段及第二验证阶段得到的曲线下面积(AUC)分别是0.992及0.985。通过对7个血清：miRNA与生存时间的分析发现,miR-21的表达水平与病人的生存期有着明显的相关性,可以作为预后因子对病人的预后起到提示作用,miR-21高表达的病人预后相对较差。通过多因素分析结果发现,miR-21是预后的独立影响因素。进一步的研究结果发现,以69例样本(胰腺癌+正常对照)进行双盲验证结果发现,该组标志物的敏感性与特异性分别为86.5%及87.5%。高于CA19-9(敏感性70.0%,特异性68.9%)及CEA(敏感性71.4%,特异性73.3%)的敏感性与特异性。以7个血清miRNA作为标志物对55例高度疑似胰腺癌的初诊病人进行检测,后通过随访经临床病理确诊诊断,该血清标志物的诊断准确率为83.64%。
通过以上研究鉴定出的7个血清(?)miRNA能够准确的区别胰腺癌与正常对照样本及慢性胰腺炎样本,该组标志物可以改进单一的分子标记物所难以克服的低特异性和低灵敏度问题,能显著提高胰腺癌的临床检出率,成为早期诊断的有效手段。7个血清(?)niRNA作为一种新奇的无创胰腺癌诊断和预后标志物具有良好的临床应用潜力。如能将血清(?)miRNA推广应用于胰腺癌以及其他肿瘤的普查、筛查工作,及临床预后及疗效预测等领域,将可能带来未来临床医学上的变革。
Pancreatic cancer (PaC) is the tourth leading cause of cancer-related deaths in western countries and has the poorest survival rate (<5%) among the common malignancies.Although surgical resection shows promise as an effective treatment for PaC, lack of effective tool for diagnosis at the early stage results in5-year survival rate from more than50%in patients with stage Ⅰ rapidly dropping to less than5%in patients with more advanced stage. Both imaging techniques and serological markers, such as carbohydrate antigen19-9(CA19-9) and carcinoembryonic antigen (CEA), are less sensitive and specific. Molecular markers in pancreatic juice, pancreatic duct brushings, duodenal aspirates, or duodenal tissue have also been used for PaC classification. These tests, however, are less practical for screening or routine clinical checkups since sample collection is invasive and difficult. In addition, it is still difficult to distinguish chronic pancreatitis (CP), a high-risk population of PaC, from PaC. Therefore, to improve the prognosis of PaC, it is urgent to develop specific and non-invasive biomarkers for PaC diagnosis, especially for early stage tumors. Detection of pancreatic cancer (PaC) especially at early stages remains a great challenge due to lack of specific biomarker. The aim of this study was to identify PaC-specific serum miRNA (miRNAs) expression profile and test its specificity and sensitivity as a biomarker for PaC diagnosis and prognosis.
The present study enrolled157patients who had been clinically classified as PaC at the time of participation, between2005and2009. In the initial biomarker screening stage, pooled serum samples from25PaC cases (Tianjin Medical University Cancer Institute and Hospital) and25matched controls(Jinling Hospital) were subjected to Solexa sequencing to select miRNAs whose expression was altered in PaC cases compared to that in controls. Subsequently, the number of serum miRNAs included as the PaC signature was refined by a two-phase experimental procedure using TaqMan probe-based qRT-PCR assay. The training phase used serum samples from the25PaC cases and25controls that had been employed for Solexa sequencing, whereas the validation phase used serum samples from an additional95PaC cases (Changhai Hospital, Ruijin Hospital, and Beijing Cancer Hospital&Institute) and81controls (Jinling Hospital). The panel of serum miRNAs selected as the PaC biomarker was further examined in the second control group comprising82CP cases (Changhai Hospital and Ruijin Hospital). Furthermore, additional37.PaC cases (First Affiliated Hospital of Nanjing Medical University) and32controls (Jinling Hospital) were analyzed in a blind fashion, in which the investigators performing the molecular analysis on the blood samples were blinded to the patients' clinical diagnosis. Finally, additional55suspicious PaC cases (Jinling Hospital) based on preliminary diagnosis were analyzed for the seven miRNA levels using the same methods. All the protocols, including the diagnosis procedure and serum collection manner, are identical in these hospitals. Written informed consent was obtained from all patients and volunteers prior to the study, and the study was approved by the ethics committee of each participating institution.
All the157patients enrolled in the present study were clinically and pathologically diagnosed with pancreatic ductal adenocarcinoma. There was no significant difference in the distribution of smoking (p=0.8704), alcohol consumption (p=0.5200), age (p=0.3406), and gender (p=0.8906) between the cancer patients and the normal control subjects. In the initial screening phase by Solexa sequencing, serum samples were pooled from25PaC patients or25healthy donors. A genome-wide expression profiling of serum miRNAs obtained by Solexa sequencing showed that PaC serum had44miRNAs upregulated and19miRNAs downregulated compared to the controls. After the selection and validation process,7miRNAs were found to have significantly different expression levels in the PaC compared to the control. This7-serum miRNA-based biomarker distinguished various stages of. PaC from cancer-free controls with high sensitivity and specificity, and also accurately discriminated PaC patients from chronic pancreatitis (CP) patients. Among the7miRNAs, level of miR-21in serum was significantly associated with overall survival of PaC. PaC patients with high levels of serum miR-21exhibited a lower survival rate compared to those with low levels of serum miR-21(p<0.05; log-rank test). Subsequently, a univariate and multivariate Cox proportional hazard regression model was performed to determine the influence of serum miRNA level as well as clinicopathological characteristics (gender, age, TNM stage, etc) on patient survival. The results showed that the miR-21expression level could serve as an independent indicator for predicting the survival rate of PaC patients.7-miRNA signature could be used to separate PaC from CP cases. Interestingly, no significant differences were observed in the levels of these seven miRNAs between CP patients and normal controls. The ROC curve also indicated that this7-miRNA-based biomarker could accurately discern CP cases from PaC cases (AUC=0.993) but not from normal controls (AUC=0.644). Furthermore, the forecast accuracy rate of the7-serum miRNA as a biomarker in discriminative diagnosis of55clinical suspicious PaC was83.64%.
The present study has identified a seven-serum miRNA-based biomarker for accurately discerning PaC cases from cancer-free controls and CP cases. The7-serum miRNA-based biomarker may serve as a novel non-invasive approach for PaC diagnosis and prognosis. Discovery of the serum miRNAs as potential biomarkers overcomes the obstacle in invasive process of tissue sample collection.
miRNA (microRNA)是一类长约19-23个核苷酸的小分子单链RNA,它由一段具有发夹结构的单链RNA前体经Drosha酶和Dicer酶的剪切后生成。miRNA通过与目标(?)nRNA分子的3’端非编码区域(3’-UTR)互补配对,使目标mRNA分子的翻译受到抑制或引起特异性的对(?)nRNA分子的切割,从而在转录后水平对靶基因的表达进行调控。大量研究成果表明,miRNA参与着生物体中很多基本生命过程的调控,在生命活动中起着非常重要的作用,miRNA分子不仅自身作为功能分子发挥作用,还广泛参与和决定基因表达调控和蛋白质翻译,进而影响细胞的新陈代谢等所有生命过程。miRNA标志物将成为疾病发生发展相关基因标志物、蛋白质标志物和代谢物标志物整体“网络”中的“结点”。虽然肿瘤组织中的miRNA可以作为一种新的肿瘤标志物,但是,为了获得肿瘤组织(?)miRNA,势必需要进行有创的手术或者穿刺等,所以组织miRNA仍然不能满足早期诊断的需要,仍然不能适用于广泛的筛查和预防。基于此,研究人员将目光投向较易获得,甚至常规体检中就可以收集到的血液。血清的检测是无创的、非侵入的,因此可以适用于普查和预防,为早期诊断服务。随着miRNA研究的不断深入,发现血清、血浆及其它体液中存在miRNA,并发现这些体液来源的miRNA能非侵入地诊断肿瘤等疾病及判断预后。
本研究收集了157份胰腺癌及138份年龄性别相匹配的正常对照。初步采用单分子微阵列(solexa)高通量小分子测序对两组病人的混合血清进行筛选,得出差异表达的血清miRNA,随后通过定量PCR (qRT-PCR)对初筛阶段差异表达的血清miRNA进行大规模、单样本、二阶段的精确定量验证。通过聚类分析、风险评分分析、曲线下面积分析评估该组血清miRNA表达谱对胰腺癌诊断的准确性及可靠性。另选取82例慢性胰腺炎作为第二对照,进一步验证该组标志物对胰腺癌病人和其高危人群慢性胰腺炎的区分能力。进一步选取69例样本(胰腺癌+正常对照)进行双盲实验验证,操作者与结果分析者均不知晓样本信息前提下进行实验及分析验证其诊断的准确性。另选取55例临床疑似胰腺癌的病例进行前瞻性分析,结合后续该55例样本的临床病理诊断来评价该组血清miRNA作为胰腺癌诊断生物标志物的准确性。
通过初步高通量的Solexa测序筛选及qRT-PCR验证过程,得到7个在胰腺癌与正常对照样本间稳定差异表达的miRNA,即：(?)niR-20a, miR-21, miR-24, miR-25, miR-99a, miR-185,及miR-191。采用风险系数评分标准进一步评价7个miRNA表达系统对胰腺癌的诊断能力。该组血清miRNA作为标志物能够将各种阶段的胰腺癌与正常对照样本以较高的敏感性和特异性区分开来,而且,同样能够准确的区分胰腺癌与慢性胰腺炎病例,表明该组标志物是胰腺癌的特异性标志物。进一步构建受试者工作特征曲线(ROC),先采用风险评分方法分别评估所有样本的7个血清miRNA的敏感性及特异性,由此构建ROC,对于第一验证阶段及第二验证阶段得到的曲线下面积(AUC)分别是0.992及0.985。通过对7个血清：miRNA与生存时间的分析发现,miR-21的表达水平与病人的生存期有着明显的相关性,可以作为预后因子对病人的预后起到提示作用,miR-21高表达的病人预后相对较差。通过多因素分析结果发现,miR-21是预后的独立影响因素。进一步的研究结果发现,以69例样本(胰腺癌+正常对照)进行双盲验证结果发现,该组标志物的敏感性与特异性分别为86.5%及87.5%。高于CA19-9(敏感性70.0%,特异性68.9%)及CEA(敏感性71.4%,特异性73.3%)的敏感性与特异性。以7个血清miRNA作为标志物对55例高度疑似胰腺癌的初诊病人进行检测,后通过随访经临床病理确诊诊断,该血清标志物的诊断准确率为83.64%。
通过以上研究鉴定出的7个血清(?)miRNA能够准确的区别胰腺癌与正常对照样本及慢性胰腺炎样本,该组标志物可以改进单一的分子标记物所难以克服的低特异性和低灵敏度问题,能显著提高胰腺癌的临床检出率,成为早期诊断的有效手段。7个血清(?)niRNA作为一种新奇的无创胰腺癌诊断和预后标志物具有良好的临床应用潜力。如能将血清(?)miRNA推广应用于胰腺癌以及其他肿瘤的普查、筛查工作,及临床预后及疗效预测等领域,将可能带来未来临床医学上的变革。
Pancreatic cancer (PaC) is the tourth leading cause of cancer-related deaths in western countries and has the poorest survival rate (<5%) among the common malignancies.Although surgical resection shows promise as an effective treatment for PaC, lack of effective tool for diagnosis at the early stage results in5-year survival rate from more than50%in patients with stage Ⅰ rapidly dropping to less than5%in patients with more advanced stage. Both imaging techniques and serological markers, such as carbohydrate antigen19-9(CA19-9) and carcinoembryonic antigen (CEA), are less sensitive and specific. Molecular markers in pancreatic juice, pancreatic duct brushings, duodenal aspirates, or duodenal tissue have also been used for PaC classification. These tests, however, are less practical for screening or routine clinical checkups since sample collection is invasive and difficult. In addition, it is still difficult to distinguish chronic pancreatitis (CP), a high-risk population of PaC, from PaC. Therefore, to improve the prognosis of PaC, it is urgent to develop specific and non-invasive biomarkers for PaC diagnosis, especially for early stage tumors. Detection of pancreatic cancer (PaC) especially at early stages remains a great challenge due to lack of specific biomarker. The aim of this study was to identify PaC-specific serum miRNA (miRNAs) expression profile and test its specificity and sensitivity as a biomarker for PaC diagnosis and prognosis.
The present study enrolled157patients who had been clinically classified as PaC at the time of participation, between2005and2009. In the initial biomarker screening stage, pooled serum samples from25PaC cases (Tianjin Medical University Cancer Institute and Hospital) and25matched controls(Jinling Hospital) were subjected to Solexa sequencing to select miRNAs whose expression was altered in PaC cases compared to that in controls. Subsequently, the number of serum miRNAs included as the PaC signature was refined by a two-phase experimental procedure using TaqMan probe-based qRT-PCR assay. The training phase used serum samples from the25PaC cases and25controls that had been employed for Solexa sequencing, whereas the validation phase used serum samples from an additional95PaC cases (Changhai Hospital, Ruijin Hospital, and Beijing Cancer Hospital&Institute) and81controls (Jinling Hospital). The panel of serum miRNAs selected as the PaC biomarker was further examined in the second control group comprising82CP cases (Changhai Hospital and Ruijin Hospital). Furthermore, additional37.PaC cases (First Affiliated Hospital of Nanjing Medical University) and32controls (Jinling Hospital) were analyzed in a blind fashion, in which the investigators performing the molecular analysis on the blood samples were blinded to the patients' clinical diagnosis. Finally, additional55suspicious PaC cases (Jinling Hospital) based on preliminary diagnosis were analyzed for the seven miRNA levels using the same methods. All the protocols, including the diagnosis procedure and serum collection manner, are identical in these hospitals. Written informed consent was obtained from all patients and volunteers prior to the study, and the study was approved by the ethics committee of each participating institution.
All the157patients enrolled in the present study were clinically and pathologically diagnosed with pancreatic ductal adenocarcinoma. There was no significant difference in the distribution of smoking (p=0.8704), alcohol consumption (p=0.5200), age (p=0.3406), and gender (p=0.8906) between the cancer patients and the normal control subjects. In the initial screening phase by Solexa sequencing, serum samples were pooled from25PaC patients or25healthy donors. A genome-wide expression profiling of serum miRNAs obtained by Solexa sequencing showed that PaC serum had44miRNAs upregulated and19miRNAs downregulated compared to the controls. After the selection and validation process,7miRNAs were found to have significantly different expression levels in the PaC compared to the control. This7-serum miRNA-based biomarker distinguished various stages of. PaC from cancer-free controls with high sensitivity and specificity, and also accurately discriminated PaC patients from chronic pancreatitis (CP) patients. Among the7miRNAs, level of miR-21in serum was significantly associated with overall survival of PaC. PaC patients with high levels of serum miR-21exhibited a lower survival rate compared to those with low levels of serum miR-21(p<0.05; log-rank test). Subsequently, a univariate and multivariate Cox proportional hazard regression model was performed to determine the influence of serum miRNA level as well as clinicopathological characteristics (gender, age, TNM stage, etc) on patient survival. The results showed that the miR-21expression level could serve as an independent indicator for predicting the survival rate of PaC patients.7-miRNA signature could be used to separate PaC from CP cases. Interestingly, no significant differences were observed in the levels of these seven miRNAs between CP patients and normal controls. The ROC curve also indicated that this7-miRNA-based biomarker could accurately discern CP cases from PaC cases (AUC=0.993) but not from normal controls (AUC=0.644). Furthermore, the forecast accuracy rate of the7-serum miRNA as a biomarker in discriminative diagnosis of55clinical suspicious PaC was83.64%.
The present study has identified a seven-serum miRNA-based biomarker for accurately discerning PaC cases from cancer-free controls and CP cases. The7-serum miRNA-based biomarker may serve as a novel non-invasive approach for PaC diagnosis and prognosis. Discovery of the serum miRNAs as potential biomarkers overcomes the obstacle in invasive process of tissue sample collection.
引文
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