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

Abstract

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. 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). 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). 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.