Molecular Classification of Suspicious Thyroid Tumors

可疑甲状腺肿瘤的分子分类

• 批准号: 6926763
• 负责人: MARTHA Allen ZEIGER
• 金额: $ 29.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926763
• 关键词: clinical research; diagnosis design /evaluation; fine needle aspiration; genotype; human subject; immunocytochemistry; in situ hybridization; microarray technology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; patient oriented research; polymerase chain reaction; technology /technique development; thyroid neoplasm

A. SPECIFIC AIMS Diagnostic Dilemma in the Differential Diagnosis of a Suspicious Thyroid Nodule. Although fine needle aspiration (FNA) cytology is the best diagnostic tool in the differential diagnosis of a thyroid nodule, it often cannot differentiate a benign from a malignant lesion. Consequently, a majority of patients with thyroid nodules require surgery because of a suspicious, but not definite, diagnosis of malignancy. Because the surgical management for benign and malignant thyroid nodules differs, patients with suspicious FNAs may be treated in a less than ideal way surgically. Some patients with benign lesions may undergo unnecessary surgery and some with malignant lesions may require a second operation for completion thyroidectomy once a diagnosis of malignancy is rendered on permanent histological section. Research Premise Although others and we have documented various genetic alterations in thyroid neoplasms, no specific alteration(s) can reliably distinguish benign from malignant lesions. We propose that specific gene expression patterns are associated with the various thyroid tumor types and that these unique expression patterns can be capitalized upon to differentiate one tumor type from another. We therefore propose to genotype by microarray analysis the benign and malignant thyroid lesions that can and often do present as "suspicious" lesions on FNA cytology. [To that end we have performed microarray analysis on 63 thyroid tumors and have selected a set of 11 genes that best discriminate benign from malignant in 4 of 8 thyroid tumor sub-types. These data will be validated and expanded to include 4 additional thyroid tumor sub-types. A panel of candidate, discriminating genes will then be validated by real time RT-PCR and in situ hybridization (ISH) of thyroid tumors, followed by both immunohistochemistry (IHC) of tissue microarrays and, immunocytochemistry (ICC) of cell blocks Prepared from thyroid cell lines and FNA samples.] The ultimate and future goal would then be to apply these results to the differential diagnosis of suspicious thyroid FNA samples in order to improve the clinical management of patients with this diagnosis. To accomplish these goals we propose the following: Specific Aim 1: To genomically define by microarray analysis benign and malignant thyroid tumors. Specific Aim 2: To validate the candidate gene sets selected in Aim 1 by real-time quantitative RT-PCR and, [in situ hybridization ISH]. Specific Aim 3: To develop immunohistochemical (IHC) assays for genes validated in Aim 2, validate these by tissue microarrays analysis (TMA) of thyroid tumors and [cell blocks prepared from paraffin-embedded thyroid cell lines, and perform immunocytochemical (ICC) assays to cell blocks prepared from FNA samples.]

A. 具体目标 可疑甲状腺结节鉴别诊断中的诊断困境。 尽管细针抽吸（FNA）细胞学是鉴别诊断甲状腺结节的最佳诊断工具，但它通常无法区分良性病变和恶性病变。因此，大多数甲状腺结节患者由于可疑但不确定的恶性肿瘤诊断而需要手术。由于良性和恶性甲状腺结节的手术治疗不同，可疑 FNA 患者的手术治疗可能不太理想。一些良性病变的患者可能会接受不必要的手术，而一些恶性病变的患者一旦永久组织学切片诊断为恶性肿瘤，可能需要第二次手术以完成甲状腺切除术。 研究场所 尽管其他人和我们已经记录了甲状腺肿瘤的各种遗传改变，但没有特定的改变可以可靠地区分良性病变和恶性病变。我们认为特定的基因表达模式与各种甲状腺肿瘤类型相关，并且可以利用这些独特的表达模式来区分一种肿瘤类型与另一种肿瘤类型。因此，我们建议通过微阵列分析对良性和恶性甲状腺病变进行基因分型，这些病变在 FNA 细胞学上可能并且经常表现为“可疑”病变。 [为此，我们对 63 个甲状腺肿瘤进行了微阵列分析，并选择了一组 11 个基因，这些基因能够最好地区分 8 种甲状腺肿瘤亚型中的 4 种的良性和恶性。这些数据将得到验证并扩展以包括另外 4 种甲状腺肿瘤亚型。然后，将通过实时 RT-PCR 和甲状腺肿瘤原位杂交 (ISH) 验证一组候选的区分基因，然后进行组织微阵列的免疫组织化学 (IHC) 和细胞块的免疫细胞化学 (ICC) 由甲状腺细胞系和 FNA 样本制备。] 最终和未来的目标是将这些结果应用于可疑甲状腺 FNA 样本的鉴别诊断，以改善对此诊断患者的临床管理。 为了实现这些目标，我们提出以下建议： 具体目标 1：通过微阵列分析从基因组角度定义良性和恶性甲状腺肿瘤。 具体目标 2：通过实时定量 RT-PCR 和[原位杂交 ISH] 验证目标 1 中选择的候选基因集。 具体目标 3：针对目标 2 中验证的基因开发免疫组织化学 (IHC) 检测，通过甲状腺肿瘤和石蜡包埋甲状腺细胞系制备的细胞块的组织微阵列分析 (TMA) 进行验证，并进行免疫细胞化学 (ICC) 检测到从 FNA 样品制备的细胞块。]