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需要临床评价的甲状腺结节。虽然细针穿刺活检（FNA）改善了甲状腺结节的处理，但它可能无法诊断，或在高达30%的病例中显示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为10%至40%，因此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，这些因素都不够准确，以确定哪些患者可疑或不确定的细针穿刺细胞学检查结果应该接受甲状腺切除术。因此，所有这些患者都需要进行诊断性甲状腺切除术才能准确诊断其疾病。只有大约20%的患者会有恶性肿瘤，但那些谁做将需要完成甲状腺切除术。我们的长期目标是确定甲状腺癌的诊断和预后分子标志物，以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甲状腺完全切除术的需要及其相关的风险和成本。这项研究背后的假设是，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的研究细胞外基质和粘附分子的cDNA阵列表达分析在良性和恶性甲状腺肿瘤。首先，我们发现细胞外基质蛋白1（ECM 1）和跨膜蛋白酶，丝氨酸4（TMPRSS 4）mRNA表达水平是准确的诊断指标，用于区分恶性和良性甲状腺肿瘤。第二，ECM 1 mRNA表达水平也与疾病程度相关。基于这些观察，本建议的实验重点是目的1）评估ECM 1和TMPRSS 4 mRNA表达分析在甲状腺结节FNA活检样品中的诊断准确性。目的2）确定ECM 1是否是分化型甲状腺癌患者无病生存和死因特异性死亡的标志物。我们将利用这些结果设计一项多中心临床试验，评估ECM 1和TMPRSS 4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.