Extracellular matrix and protease markers of malignant thyroid neoplasm

描述（由申请人提供）：大约10%的美国人口将在其一生中发展为需要临床评估的甲状腺结节。虽然细针穿刺（FNA）活检改善了甲状腺结节的治疗，但在高达30%的病例中，它可能是非诊断性的，或表现出不确定和可疑的细胞学特征。由于FNA活检结果不确定和可疑的患者患甲状腺癌的风险在10%到40%之间，研究人员评估了术前临床、影像学和细胞学因素，以更好地预测甲状腺癌的风险。不幸的是，这些因素都不足以准确地确定哪些FNA细胞学表现可疑或不确定的患者应该接受甲状腺切除术。因此，所有这些患者都需要诊断性甲状腺切除术以准确诊断其疾病。这些患者中只有大约20%会有恶性肿瘤，但那些有恶性肿瘤的患者将需要完全切除甲状腺。我们的长期目标是确定甲状腺癌的诊断和预后分子标记物，准确区分良性和恶性甲状腺结节，从而消除或减少诊断性甲状腺切除术或完全甲状腺切除术的需要及其相关的风险和成本。提出的研究背后的假设是，差异表达的基因可以用来区分良性和恶性甲状腺结节，并作为疾病侵袭性的标志。这一假设是基于我们对良恶性甲状腺肿瘤细胞外基质和粘附分子的cDNA阵列表达分析。首先，我们发现细胞外基质蛋白1 （ECM1）和跨膜蛋白酶、丝氨酸4 (TMPRSS4) mRNA表达水平是区分甲状腺肿瘤良恶性的准确诊断指标。其次，ECM1 mRNA表达水平也与疾病程度相关。基于这些观察结果，本课题的实验重点是：1)评估甲状腺结节FNA活检标本中ECM1和TMPRSS4 mRNA表达分析的诊断准确性。目的2)确定ECM1是否是分化型甲状腺癌患者无病生存和病因特异性死亡率的标志。我们将利用这些结果设计一项多中心临床试验，评估ECM1和TMPRSS4表达在甲状腺肿瘤患者中的诊断和预后价值。

DESCRIPTION (provided by applicant): Approximately 10% of the US population will develop a thyroid nodule that requires clinical evaluation during their lifetime. Although fine needle aspiration (FNA) biopsy has improved the management of thyroid nodules, it may be nondiagnostic, or show indeterminate and suspicious cytologic features in up to 30% of cases. Because the risk of thyroid cancer is anywhere from 10% to 40% in patients with indeterminate and suspicious FNA biopsy results, investigators have evaluated preoperative clinical, imaging and cytologic factors to better predict the risk of thyroid cancer. Unfortunately, none of these factors are accurate enough to determine which patients with suspicious or indeterminate FNA cytologic findings should undergo thyroidectomy. Consequently, all of these patients require a diagnostic thyroidectomy in order to accurately diagnose their disease. Only about 20% of these patients will have a malignant tumor, but those who do will require a completion thyroidectomy. Our long-term goal is to identify diagnostic and prognostic molecular markers of thyroid cancer that would accurately distinguish benign from malignant thyroid nodules, thus eliminating or reducing the need for diagnostic thyroidectomy or completion thyroidectomy and their associated risks and costs. The hypothesis behind the proposed research is that differentially expressed genes can be used to distinguish benign from malignant thyroid nodules, and as markers of disease aggressiveness. This hypothesis is based on our studies of extracellular matrix and adhesion molecules using cDNA array expression analysis in benign and malignant thyroid neoplasms. First, we have found that the level of extracellular matrix protein 1 (ECM1) and transmembrane protease, serine 4 (TMPRSS4) mRNA expression are accurate diagnostic markers for distinguishing malignant from benign thyroid neoplasm. Second, the level of ECM1 mRNA expression also correlated with the extent of disease. Based on these observations, the experimental focus of this proposal are Aim 1) To evaluate the diagnostic accuracy of ECM1 and TMPRSS4 mRNA expression analysis in FNA biopsy samples of thyroid nodules. Aim 2) To determine if ECM1 is a marker of disease-free survival and cause-specific mortality in patients with differentiated thyroid cancer. We will use these results to design a multicenter clinical trial evaluating the diagnostic and prognostic value of ECM1 and TMPRSS4 expression in patients with thyroid neoplasm.