血管生成调节基因在甲状腺恶性肿瘤中的诊断和预后价值

Diagnostic and prognostic value of angiogenesis-modulating genes in malignant thyroid neoplasms.

作者信息

Kebebew Electron, Peng Miao, Reiff Emily, Duh Quan-Yang, Clark Orlo H, McMillan Alex

机构信息

Endocrine Surgery and Oncology Program, University of California, San Francisco Comprehensive Cancer Center, CA 94143-1674, USA.

出版信息

Surgery. 2005 Dec;138(6):1102-9; discussion 1109-10. doi: 10.1016/j.surg.2005.05.025.

DOI:10.1016/j.surg.2005.05.025

PMID:16360397

Abstract

BACKGROUND

Angiogenesis is an essential biologic event in the pathogenesis of human malignancies. We postulated that expression analysis of genes that modulate angiogenesis would identify differentially expressed genes that would help to distinguish benign from malignant thyroid neoplasms and serve as markers of aggressive differentiated thyroid cancer.

METHODS

A complementary DNA (cDNA) array with 96 genes that modulate angiogenesis was used to identify differentially expressed genes (2-fold higher or lower) in malignant versus benign thyroid neoplasms. Real-time quantitative polymerase chain reaction was used to confirm cDNA array expression data in 123 patients (4 normal thyroid, 26 hyperplastic nodules, 27 follicular adenomas, 23 follicular cancers, 18 follicular variant of papillary cancers, 25 papillary cancers).

RESULTS

Twenty-two genes were upregulated in malignant thyroid neoplasms by cDNA array analysis, but only 13 genes had higher messenger RNA (mRNA) expression levels in malignant than in benign thyroid neoplasms by real-time quantitative polymerase chain reaction (P < or = .04). Of the 13 differentially expressed genes, the combined use of angiopoietin 2 (ANGPT2) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNA expression levels was best for distinguishing malignant from benign thyroid neoplasms, with a sensitivity of 90%, specificity of 85%, positive predictive value of 75%, and negative predictive value of 94%. Epidermal growth factor receptor and ephrin B2 mRNA expression was elevated in higher TNM stage neoplasms and in patients with high-risk AMES (Age, distant Metastasis, Extrathyroidal invasion, and tumor Size) differentiated thyroid cancers (P < or = .005).

CONCLUSIONS

Angiopoietin 2 and tissue inhibitor of metalloproteinase 1 are diagnostic markers of malignant thyroid nodules and could improve the diagnostic accuracy of FNA biopsy. Epidermal growth factor receptor and ephrin B2 are markers of aggressive differentiated thyroid cancer.

摘要

背景

血管生成是人类恶性肿瘤发病机制中的一个重要生物学事件。我们推测，对调节血管生成的基因进行表达分析，将能够识别出差异表达基因，这些基因有助于区分甲状腺良性和恶性肿瘤，并可作为侵袭性分化型甲状腺癌的标志物。

方法

使用包含96个调节血管生成基因的互补DNA（cDNA）阵列，来识别恶性与良性甲状腺肿瘤中差异表达的基因（表达水平相差2倍或以上）。采用实时定量聚合酶链反应，对123例患者（4例正常甲状腺组织、26例增生性结节、27例滤泡性腺瘤、23例滤泡癌、18例滤泡型乳头状癌、25例乳头状癌）的cDNA阵列表达数据进行验证。

结果

通过cDNA阵列分析，在恶性甲状腺肿瘤中有22个基因上调，但通过实时定量聚合酶链反应，只有13个基因在恶性甲状腺肿瘤中的信使核糖核酸（mRNA）表达水平高于良性甲状腺肿瘤（P≤0.04）。在这13个差异表达基因中，血管生成素2（ANGPT2）和金属蛋白酶组织抑制剂1（TIMP1）mRNA表达水平联合使用，对区分甲状腺恶性和良性肿瘤效果最佳，敏感性为90%，特异性为85%，阳性预测值为75%，阴性预测值为94%。表皮生长因子受体和ephrin B2 mRNA表达，在TNM分期较高的肿瘤以及具有高危AMES（年龄、远处转移、甲状腺外侵犯和肿瘤大小）的分化型甲状腺癌患者中升高（P≤0.005）。