Predicting continuous values of prognostic markers in breast cancer from microarray gene expression profiles

The prognostic and treatment-predictive markers currently in use for breast cancer are commonly based on the protein levels of individual genes (e.g., steroid receptors) or aspects of the tumor phenotype, such as histological grade and percentage of cells in the DNA synthesis phase of the cell cycle. Microarrays have previously been used to classify binary classes in breast cancer such as estrogen receptor (ER)-alpha status. To test whether the properties and specific values of conventional prognostic markers are encoded within tumor gene expression profiles, we have analyzed 48 well-characterized primary tumors from lymph node-negative breast cancer patients using 6728-element cDNA microarrays. In the present study, we used artificial neural networks trained with tumor gene expression data to predict the ER protein values on a continuous scale. Furthermore, we determined a gene expression profile-directed threshold for ER protein level to redefine the cutoff between ER-positive and ER-negative classes that may be more biologically relevant. With a similar approach, we studied the prediction of other prognostic parameters such as percentage cells in the S phase of the cell cycle (SPF), histological grade, DNA ploidy status, and progesterone receptor status. Interestingly, there was a consistent reciprocal relationship in expression levels of the genes important for both ER and SPF prediction. This and similar studies may be used to increase our understanding of the biology underlying these markers as well as to improve the currently available prognostic markers for breast cancer.     

Bcl-2和Bax的表达与乳腺癌转移及预后的关系

目的　探讨Bcl 2和Bax基因在乳腺癌中的表达及与乳腺癌淋巴结转移、预后的关系。方法　应用SP免疫组化染色方法 ,检测 4 0例乳腺癌组织中Bcl 2、Bax的表达情况。结果　无淋巴结转移组Bcl 2阳性表达率与淋巴结转移组有显著差异 (P <0 .0 5 ) ,10年以上存活组Bcl 2阳性表达率与 10年以下存活组有显著差异 (P <0 .0 1)。无淋巴结转移组Bax阳性表达率与淋巴结转移组有显著差异 (P <0 .0 5 ) ,10年以上存活组Bax阳性表达率与 10年以下存活组有显著差异 (P <0 .0 5 )。结论　Bcl 2和Bax表达与乳腺癌淋巴结转移、预后关系密切 ,Bcl 2提示高表达、Bax低表达的乳腺癌患者有低的转移率及好的预后。     

结肠癌淋巴结转移基因谱表达差异分析

目的探讨人结肠癌细胞系SW480、SW620基因谱的表达差异。方法针对NCBI的GEO数据库中编号为GDS756的基因芯片表达数据,用GSEA软件进行基因集富集分析及领头亚群分析,利用FunRich分析软件针对SW480、SW620细胞领头亚群基因进行验证性功能注释,STRING在线分析系统对显著性富集基因集领头亚群基因进行生物网络分析,获得SW480、SW620细胞中心节点基因,并将中心节点基因与高重叠领头亚群基因进行联合分析,以获得参与多功能的中心节点基因。结果GSEA软件分析筛选出SW480细胞显著性富集基因集12个,领头亚群基因491个,高重叠基因7个;SW620细胞显著性富集基因集80个,领头亚群基因870个,高重叠基因6个。对显著性富集基因集领头亚群基因进行生物网络分析筛选出SW480、SW620细胞相关中心基因数目分别为5个及8个;结合GSEA及生物网络分析结果,获得SW620细胞2个参与多功能调控的核心基因TOP2A、CDK1。结论遗传背景相同的结肠癌SW620细胞与SW480细胞具有不同的基因功能分布特点,SW620细胞多功能中心节点基因TOP2A、CDK1与结肠癌发展相关信号通路高度相关。     

多指标联合检测对乳腺癌的诊断价值

目的探讨溶血磷脂酸(LPA),肿瘤特异性生长因子(TSGF)和糖链抗原153(CA153)联合检测对乳腺癌的诊断价值。方法检测97例乳腺癌患者(乳腺癌组)、43例良性乳腺疾病患者(良性疾病组)及50例健康女性(对照组)血清LPA、TSGF和CA153水平,计算各指标单独及联合检测对乳腺癌的诊断灵敏度和特异度。结果乳腺癌组LPA、TSGF和CA153水平均高于良性疾病组和对照组(P0.05);LPA、TSGF和CA153联合检测对乳腺癌的诊断灵敏度、特异度高于单项检测(P0.05)。结论肿瘤标志物联合检测可提高对乳腺癌的诊断灵敏度、特异度,为疾病的诊断提供可靠依据。     

CerbB-2在乳腺癌中的表达与转移的相关性分析

目的分析乳腺癌CerbB-2的表达与年龄、肿瘤大小、病理学类型、腋窝淋巴结转移及远处转移的相关性。方法应用免疫组化sP法对69例原发性乳腺癌行根治及改良根治术的标本进行了CerbB-2的检测,并进行统计学分析。结果CerbB-2阳性表达率为73．9％（51／69）;CerbB-2的阳性表达率与淋巴结转移及有远处转移有关（P〈0．05）,而与患者年龄、肿瘤大小、病理学类型无关（P〉0．05）。结论CerbB-2的阳性表达与淋巴结转移程度呈正相关,与年龄、肿瘤大小、病理学类型及远处转移不相关。CerbB-2的过表达与淋巴结转移及远处转移相关。CerbB-2可作为判断乳腺癌预后的指标。     

3种肿瘤标志物检测在乳腺癌术后随访中的价值

目的探讨乳腺癌术后随访中糖链抗原(CA)153、CA125及癌胚抗原(CEA)的价值。方法选取2013年8月至2014年8月该院收治的98例乳腺癌复发转移患者,107例乳腺癌未复发转移患者作为研究对象,分别检测其血清CA153、CA125及CEA,并进行统计学分析。结果复发转移组CA153、CA125及CEA水平均明显高于未复发转移组,差异有统计学意义(P0.01)。CA153曲线下面积(AUC)大于CA125和CEA,当cut off值为21.79ng/mL时,Youden指数最大,敏感度为80.8%,特异性为91.6%。logistic回归分析表明,CA153对乳腺癌复发转移有较高的预测效能。结论 CA153、CA125及CEA可为临床早期、准确诊断乳腺癌复发转移提供参考依据,且CA153的诊断价值优于CA125及CEA。     

4种肿瘤标志物联合检测对乳腺癌的诊断价值

目的探讨血清肿瘤标志物CA153、CA125、CA199、CEA联合检测对乳腺癌早期诊断的价值。方法采用化学发光法分别检测乳腺癌和乳腺良性疾病患者血清中CA153、CA125、CA199、CEA的水平。结果 CA153、CA125、CA199、CEA 4种肿瘤标志物联合检测乳腺癌患者与单独检测相比灵敏度明显提高(均P0.01)。结论联合检测乳腺癌患者血清标志物CA153、CA125、CA199、CEA的阳性率、敏感性有较大幅度的提高,四项肿瘤标志物的联合检测虽不能作为乳腺癌的特异性指标,但可为临床早期发现、诊断乳腺癌提供十分重要的依据。     

乳腺癌相关生物标志物

乳腺癌是一种多因素疾病，在其发生、发展过程中伴随许多基因和蛋白的改变。通过对这些生物标志物的阐释，可以更深入地认识乳腺癌的生物学行为。临床常用的一些乳腺癌相关标志物ER、PR、HER2、CA15．3和新近研究的端粒酶、PSA、乳腺珠蛋白、TPS等生物标志物，对乳腺癌有提示预后、评估疗效、监测转移复发及术前诊断的作用。     

乳头溢液肿瘤标志物联合细胞学检查对乳腺癌的诊断价值

目的评价乳头溢液癌胚抗原(CEA)、糖链抗原125(CA125)及细胞学联合检测对乳腺癌的诊断价值。方法随机选择128例乳头溢液患者和40例正常分娩产妇进行乳头溢液或乳汁CEA、CA125和细胞学检查。结果乳腺癌患者乳头溢液CEA、CA125水平高于正常分娩产妇和乳腺良性病变患者(P<0.05),良性病变患者乳头溢液CEA、CA125水平高于正常分娩产妇(P<0.05);CEA、CA125或细胞学检查单独检测的诊断灵敏度低于各指标联合检测,但诊断特异度高于联合检测。结论乳头溢液CEA、CA125、细胞学检查联合检测有助于提高乳腺癌诊断灵敏度,减少漏诊率。     

CD34表达与乳腺癌浸润和转移关系研究

目的探讨乳腺癌浸润、转移过程中CD34表达及微血管密度的意义。方法采用免疫组织化学方法检测60例乳腺癌患者癌组织、癌旁2cm乳腺组织及距癌组织5cm以上正常乳腺组织中CD34的表达情况,检测3种组织中CD34标记的微血管密度。结果乳腺癌组织的微血管密度值（54．60±10．54）明显高于癌旁组织（33．05±7．70）和正常乳腺组织（25．40±5．71）,差异均有统计学意义（P〈0．01）。结论CD34阳性表达与乳腺癌血管生成有一定相关性。     

散发性乳腺癌中BRCAl基因甲基化状况及其与蛋白表达的关系

目的探讨散发性乳腺癌中BRCA l基因异常甲基化状况及其与蛋白表达的关系,进而研究散发性乳腺癌中BRCA l基因异常的表遗传学作用。方法用甲基特异性聚合酶链反应(PCR)和免疫组织化学(SP)法研究乳腺癌组织、癌旁正常组织中BRCA l基因启动子甲基化状况及蛋白表达情况。结果在52例散发性乳腺癌中,BRCA l甲基化率为29%,BRCA l蛋白表达下降率为33%;15例BRCA l发生甲基化的癌组织标本中BRCA l的表达下降率为87%,而37例BRCA l未发生甲基化的癌组织中BRCA l蛋白表达下降率11%。在肿瘤分级中,T3分级患者的肿瘤组织中BRCA l甲基化率(45%)及表达下降率(60%)均分别高于T1 T2分级患者肿瘤组织的BRCA l甲基化率(19%)和表达下降率(16%);有淋巴结转移患者的肿瘤组织中BRCA l甲基化率(46%)及蛋白表达下降率(50%)均分别高于无淋巴结转移的甲基化率(14%)和表达下降率(18%)。结论BRCA l基因表遗传学改变是其蛋白表达下降乃至失活的重要原因,并且与散发性乳腺癌的恶性进程和淋巴结转移密切相关。     

散发性乳腺癌中BRCAl基因甲基化状况及其与蛋白表达的关系

目的探讨散发性乳腺癌是BRCA1基因异常甲基化状况及其与蛋白表达的关系，进而研究散发性乳腺癌中BRCA1基因异常的表遗传学作用。方法用甲基特异性聚合酶链反应（PCR）和免疫组织化学（SP）法研究乳腺癌组织、癌旁正常组织中BRCA1基因扁动子甲基化状况及蛋白表达情况。结果在52例散发性乳腺癌中，BRCA1甲基化率为29％，BRCA1蛋白表达下降率为33％；15例BRCA1发生甲基化的癌组织标本中BRCA1的表达下降率为87％，而37例BRCA1未发生甲基化的癌组织中BRCA1蛋白表达下降率11％。在肿瘤分级中，T3分级患者的肿瘤组织中BRCA1甲基化率（45％）及表达下降率（60％）均分别高于T1＋1、2分级患者肿瘤组织的BRCA1甲基化率（19％）和表达下降率（16％）；有淋巴结转移患者的肿瘤组织中BRCA1甲基化牢（46％）及蛋白表达下降率（50％）均分别高于无淋巴结转移的甲基化率（14％）和表达下降率（18％）。结论BRCA1基因表遗传学改变是其蛋白表达下降乃至失活的重要原因，并且与散发性乳腺癌的恶性进程和淋巴结转移密切相关。     

血清肿瘤标记物与HER2阳性乳腺癌骨转移的相关性研究

目的观察人类表皮生长因子受体2(HER2)阳性乳腺癌的肿瘤标记物水平与骨转移的相关性。方法收集确诊为HER2阳性浸润性乳腺癌的100例患者,根据有无骨转移分为2组:骨转移组(n=40),未骨转移组(n=60)。采用ELISA法监测患者入院时、随访发生骨转移时血清糖类抗原(CA153)和癌胚抗原(CEA)水平,观察2组患者年龄、病理分型、血清肿瘤标记物和赫赛汀的应用情况等,比较2组患者上述指标的差异。采用受试者工作特征(ROC)曲线预测血清CA153、CEA对HER2阳性乳腺癌骨转移的价值。结果 HER2阳性乳腺癌患者中,骨转移组和未骨转移组入院时血清CEA、CA153水平差异无统计学意义(P0.05),ROC曲线发现血清CEA水平(AUC 0.72,95%CI0.63~0.81,P=0.01)和CA153水平(AUC 0.67,95%CI 0.60~0.77,P=0.03)为预测预测骨转移的因素。其中CA15317.2U/mL预测HER2阳性乳腺癌患者骨转移的敏感度为78.8%,特异度为45.0%;CEA2.64μg/L预测骨转移的敏感度为75.8%,特异度为43.3%。结论血清CA153和CEA水平对HER2阳性乳腺癌的骨转移有一定的预测价值。     

TGF-β upregulates miR-181a expression to promote breast cancer metastasis

Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β–regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.     

某些肿瘤标志物基因表达检测在胃肠道恶性肿瘤中的意义

近年,一些肿瘤标志物已被证实与胃肠道恶性肿瘤转移及患者预后密切相关。本文着重介绍经典的肿瘤标志物——癌胚抗原（CEA）和细胞角蛋白20（cytokeratin 20,CK20）、基质金属蛋白酶-2（MMP-2）及其抑制剂、生存素（survivin）等肿瘤标志物的结构、功能及其基因表达监测在恶性肿瘤转移和复发方面的应用进展。     

Biomarkers, tumor markers and prognostic markers in breast cancer

Biomarkers are measured in the management of breast cancer patients for the following purposes: (1) early detection, (2) monitoring of advanced breast cancer patients, (3) prediction of prognosis, and (4) prediction of therapeutic response. Summarized results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 concerning the present status of tumor marker measurement in Japan and usefulness of tumor markers for the evaluation for therapeutic response are presented. Significance of two prognostic markers, vessel invasion and HER2 status were discussed at the 9th St Gallen International Consensus Meeting in 2005. Current status, clinical significance, problems and future directions on predictive markers for response to endocrine therapy and cytotoxic chemotherapy are also discussed.     

Smoothened activates breast cancer stem-like cell and promotes tumorigenesis and metastasis of breast cancer

Smoothened (Smo) is a G protein-coupled receptor protein encoded by the Smo gene of the hedgehog signalling pathway, which is thought to play an important role in maintaining organ patterning, cell differentiation and self-renewal. The possible role of Smo in the process of tumorigenesis and metastasis of breast cancer still remains unclear. The present experiments were to investigate the effect of Smo on activating breast cancer stem-like CD44⁺CD24⁻ cells and the tumorigenesis and metastasis of breast cancer. By injected CD44⁺CD24⁻ cells (1 × 10⁴) into the cleared fat pad of NOD/SCID mice, it was observed that CD44⁺CD24⁻ cells possess higher tumor-initiating capacity and metastasis properties than equal numbers of non-CD44⁺CD24⁻ cells. The mRNA and protein expressions of Smo in CD44⁺CD24⁻ cells were higher than those in non-CD44⁺CD24⁻ cells, indicating that Smo may play a role in maintaining breast cancer stem cell features. qRT–PCR results revealed that expressions of STAT3, Bcl-2 and cyclinD1 mRNA in MCF-7 cells were decreased after transfected by Smo siRNA. In addition, the expressions of MMP-2 and MMP-9 were downregulated in MCF-7 cells after Smo expression was inhibited. Smo inhibition may be a possible therapeutic target that potentially suppresses breast tumor formation and development.     

超声引导细针抽吸活组织检查探测乳腺癌前哨淋巴结转移

目的 分析皮下注射超声造影剂对探测乳腺癌患者前哨淋巴结及应用细针穿刺抽吸的意义;探讨乳腺癌前哨淋巴结细针穿刺抽吸的临床价值。 方法 收集经病理证实的乳腺癌患者32例。超声造影后观察前哨淋巴结,记录数目,进行细针穿刺抽吸检测淋巴结转移情况,并与手术病理结果进行比较。 结果 超声造影对前哨淋巴结的检出率为78.13%(25/32)。前哨淋巴结细针穿刺抽吸细胞学病理检查的敏感度为84.00%,特异度为100%,准确率为87.50%。 结论 乳腺癌前哨淋巴结细针抽吸在乳腺癌前哨淋巴结分期中有广阔的应用前景。