Genome-wide Exploration of DNA Methylation Markers for Thyroid Cancer

描述（申请人提供）：甲状腺癌是最常见的内分泌恶性肿瘤，近年来发病率迅速上升，这在很大程度上归因于甲状腺结节诊断的增加。在甲状腺肿瘤医学的几个领域中，患者管理的效率和有效性受到当前标准方法的限制。例如，广泛用于甲状腺结节评估的细针穿刺活检（FNAB）经常产生不确定的细胞学结果，导致不必要的甲状腺手术;用于监测甲状腺癌复发的标准血清甲状腺球蛋白（Tg）检测经常受到血清中存在抗Tg自身抗体的阻碍;目前使用临床病理学标准对甲状腺癌的预后评估通常是不确定的，特别是在术前。新的甲状腺诊断和预后分子标志物，如果可用的话，可以帮助绕过这些临床障碍。由于异常的DNA甲基化模式通常与人类癌症特异性相关，我们假设独特的DNA甲基化模式或改变也存在于甲状腺癌中，并可用作这种癌症的可靠分子标记。为了验证这一假设，在本项目中，我们建议使用最近开发的功能强大的450 K DNA甲基化微阵列系统来进行全基因组搜索甲状腺肿瘤中的异常DNA甲基化改变，以确定具有最高诊断和预后潜力的最突出的DNA甲基化标记物，这些标记物对甲状腺癌具有最佳的特异性和敏感性。然后我们将 在从甲状腺肿瘤患者收集的FNAB和血清标本上进行测试，目的是建立用于甲状腺结节和甲状腺癌管理的新型临床诊断和预后分子测试。该项目代表了一种新的方法，使用强大的实验系统来识别甲状腺癌的DNA甲基化分子标志物，预计将对目前的甲状腺肿瘤医学实践产生重大影响。研究团队及其实验室经验丰富，并配备了成功进行拟议研究所需的技术专业知识和甲状腺肿瘤患者标本。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy with a rapid rising incidence in recent years, which is largely attributable to the increased diagnosis of thyroid nodules. There are several areas in thyroid tumor medicine in which efficiency and effectiveness of patient management are limited with the current standard approaches. For example, the widely used fine needle aspiration biopsy (FNAB) for thyroid nodule evaluation often yields indeterminate cytological findings, leading to unnecessary thyroid surgery; the standard serum thyroglobulin (Tg) testing to monitor thyroid cancer recurrence is often hampered by the presence of autoantibodies against Tg in the serum; and the current prognostic evaluation of thyroid cancer using clinicopathological criteria is often uncertain, particularly preoperatively. Novel thyroid diagnostic and prognostic molecular markers, if available, could help circumvent these clinical obstacles. As aberrant DNA methylation patterns are often specifically associated with human cancers, we hypothesize that unique DNA methylation patterns or alterations also exist in thyroid cancer and could be used as reliable molecular markers for this cancer. To test this hypothesis, in the present project we propose to use a recently developed powerful 450K DNA methylation microarray system to perform genome-wide search for aberrant DNA methylation alterations in thyroid tumors to identify panels of most prominent DNA methylation markers that have the highest diagnostic and prognostic potential with the best specificities and sensitivities for thyroid cancer. We will then test them on FNAB and serum specimens collected from thyroid tumor patients with the goal to establish novel clinical diagnostic and prognostic molecular tests for the management of thyroid nodules and thyroid cancer. This project represents a novel approach using a powerful experimental system to identifying DNA methylation molecular markers for thyroid cancer, which is expected to have a significant impact on the current practice of thyroid tumor medicine. The research team and their laboratory are well experienced and equipped with both technical expertise and thyroid tumor patient specimens required to successfully pursue the proposed studies.