Molecular-guided Risk Stratification of Thyroid Nodules and Cancer

项目摘要-项目4 项目4是一个新项目，旨在解决甲状腺癌流行问题。高分化甲状腺癌是 以惊人的速度增长。在过去的3年里，甲状腺癌的发病率增加了3倍。 几十年然而，这些患者的死亡率仍然非常低（估计约为2%）。因此，我们认为， 对所有患有甲状腺癌的患者进行甲状腺切除术可能不是必要的。这个项目 解决了与甲状腺癌检测和管理相关的两个主要问题。首先，我们将使用next 代测序，以开发和验证分子测试，可以更准确地区分 甲状腺癌和良性结节患者的穿刺活检结果是不确定的。这种分子 该测试分析了62个个体基因的表达和/或突变，并建立在我们以前的经验基础上 用一小部分基因诊断甲状腺癌。在第二个目标中，我们将评估我们的能力， 分子检测以区分低风险甲状腺癌和更具侵袭性（高风险）的甲状腺癌。在 为了实现这一目标，我们将首先询问从患有以下疾病的患者中获得的组织样本： 接受甲状腺癌手术，然后出现疾病复发或远处转移。 同时，我们将启动一项临床试验，观察小型甲状腺癌患者。例小 癌症将先进行分子检测，然后进行观察。高风险的分子特征 疾病将由在观察期间进展的患者的肿瘤确定。这 然后，信息将用于通知试验的第二阶段，该阶段将使用分子签名， 将患者分为高风险和低风险疾病，分别进行手术或观察。 目的1：验证基于NGS的突变标记物组可以可靠地诊断 甲状腺结节癌本目标旨在开发和验证一种新的分子分析测试， 准确预测甲状腺结节是恶性还是良性。我们将在2015年开发分子测试， 匹兹堡大学，然后验证该测试在其他8个学术中心的效用。 目的2：验证高危和低危分化型甲状腺癌具有不同的分化程度的假设。 可以在FNA样本中检测到突变谱，并用于指导患者管理。这 Aim由两部分组成，第一个子目标旨在使用分子检测来表征来自 侵袭性疾病患者（经历癌症复发或发生转移）。第二个子- aim扩展了这些数据，以开发和实施一项前瞻性临床试验， 对癌症进行观察而不是手术。这项试验的数据将证实分子检测可以 用于将甲状腺癌分为低风险亚型。

Project Summary - Project 4 Project 4 is a new project that addresses the epidemic of thyroid cancer. Well-differentiated thyroid cancer is increasing at an alarming rate. There has been a 3-fold increase in incidence of thyroid cancer in the past 3 decades. However, the mortality for these patients has remained very low (estimated to be ~2%). Therefore, performing a thyroidectomy for all patients with that thyroid cancer may not be necessary. This project addresses two major issues relevant to the thyroid cancer detection and management. Firstly, we will use next generation sequencing to develop and validate a molecular test that can more accurately distinguish between thyroid cancer and benign nodules in patients with needle biopsy results that are indeterminate. This molecular test analyses the expression and/or mutation of 62 individual genes and builds on our previous experience using a smaller panel of genes to diagnose thyroid cancer. In the second Aim, we will evaluate the ability of our molecular testing to differentiate low-risk thyroid cancers from more aggressive (high-risk) thyroid cancers. In order to accomplish this goal, we will first interrogate tissue samples obtained from patients who have undergone surgery for thyroid cancer, and then experience disease recurrence or distant metastases. Simultaneously, we will initiate a clinical trial to observe patients with small thyroid cancers. Patients with small cancers will undergo upfront molecular testing and then will be observed. A molecular profile of high-risk disease will be determined by the tumors from patients who progress during the observation period. This information will then be used to inform the second phase of the trial, which will use the molecular signature to separate patients into high-risk and low-risk disease for surgery or observation, respectively. Aim 1: To test the hypothesis that the NGS-based panel of mutational markers can reliably diagnose cancer in thyroid nodules. This Aim seeks to develop and validate a novel molecular analytic test that can accurately predict which thyroid nodules are malignant versus benign. We will develop the molecular test at the University of Pittsburgh and then validate the utility of this test in 8 other academic centers. Aim 2: To test the hypothesis that high-risk and low-risk differentiated thyroid cancers have distinct mutational profiles that can be detected in FNA samples and utilized to guide patient management. This Aim consists of two parts, the first sub-aim seeks to use molecular testing to characterize tissues derived from patients with aggressive disease (experience recurrence of cancer or develop metastases). The second sub- aim extends these data to develop and implement a prospective clinical trial that provides patients with small cancers to have observation instead of surgery. The data from this trial will validate that molecular testing can be used to stratify thyroid cancers into a low-risk subtype.