Validation of epigenomic biomarkers for thyroid cancer diagnostics

项目摘要/摘要 每年，美国有多达5万名患者接受不必要的甲状腺切除术。这些是不必要的 甲状腺切除术是由于术前很难区分良性甲状腺结节和甲状腺。 癌症。在初步数据中，我们开发了一种表观遗传学测试，显示出区分良性和良性的前景 恶性甲状腺结节。在这里，我们将严格测试和验证我们的表观遗传生物标记物的能力 评估甲状腺结节的生物侵袭性，并确定新的表观遗传学测试是否将 改进甲状腺结节管理，以消除不必要的甲状腺切除术。电流分子 对不明原因的甲状腺结节的诊断虽然提供了一些改进，但并没有消除 不必要的甲状腺切除术。目前的分子诊断是基于分子水平上的差异 正常甲状腺组织和甲状腺癌。然而，良性甲状腺结节可以包含许多分子。 包括基因融合和突变在内的改变。因此，超过一半的甲状腺结节患有严重的癌症 根据目前的分子分类，甲状腺切除术后的风险被发现是良性的。在我们出版的 初步数据，我们对109例手术切除的甲状腺进行了全基因组DNA甲基化分析。 结节和邻近的良性组织。我们发现良性结节的DNA甲基化模式不同 来自甲状腺癌和正常甲状腺。基于良性结节的DNA甲基化模式和 甲状腺癌特有的DNA甲基化模式，我们开发了诊断DNA甲基化签名 (DDMS)鉴别良恶性结节的方法。在一项回溯性的试点研究中 在1R21CA223367下运行，进一步开发了DDMS-2。我们测试了DDMS-2的能力 用于鉴别手术切除的甲状腺结节良恶性的方法(n=121)。在这项初步研究中，DDMS- 2的阳性预测值(PPV)为96%，阴性预测值(NPV)为98%。引导式 根据我们的初步数据，我们假设DDMS(I)可以成功地用于分子甲状腺癌 术前甲状腺结节的诊断学；(Ii)与 目前的甲状腺癌分子检测和(Iii)可能会影响医生对消除 不必要的甲状腺切除术。我们将通过以下具体目标，实现总体目标： 目的1：对DDMS-2分析方法进行分析验证。目的2：确定DDMS-2的准确度 从7个医学中心获得的预期队列包含1450个甲状腺结节愿望，包括 细胞病理学不确定的800个愿望。目的3：比较DDMS的诊断准确性。 2和两种目前的甲状腺癌分子诊断方法，并评估如何了解 DDMS-2结果影响甲状腺结节的临床处理。一种更准确的检测方法的发展 鉴别良、恶性甲状腺结节将解决目前的临床局限性，并减少 不必要的甲状腺切除手术和相关的疾病。

PROJECT SUMMARY/ABSTRACT Each year, up to 50,000 patients in the United States receive unnecessary thyroidectomies. These unnecessary thyroidectomies are due to difficulties in preoperatively distinguishing benign thyroid nodules from thyroid cancers. In preliminary data, we developed an epigenetic test that shows promise to distinguish benign versus malignant thyroid nodules. Here, we will rigorously test and validate the ability of our epigenetic biomarkers to evaluate the biologic aggressiveness of thyroid nodules and determine whether the new epigenetic testing will improve thyroid nodule management towards the eradication of unnecessary thyroidectomies. Current molecular diagnostics for indeterminate thyroid nodules, while providing some improvement, have not eliminated the unnecessary thyroidectomies. Current molecular diagnostics are based on molecular differences between normal thyroid tissue and thyroid cancer. However, benign thyroid nodules can contain many molecular alterations including gene fusions and mutations. As a result, over half of thyroid nodules with a significant cancer risk according to the current molecular classifiers are found to be benign after thyroidectomy. In our published preliminary data, we performed a genome-wide DNA methylation analysis of 109 surgically excised thyroid nodules and adjacent benign tissue. We found that the DNA methylation pattern in benign nodules is different from thyroid cancer and normal thyroid. Based on the DNA methylation pattern specific to benign nodules and the DNA methylation pattern specific to thyroid cancer, we developed the Diagnostic DNA Methylation Signature (DDMS) approach to distinguish between benign versus malignant nodules. In a retrospective pilot study performed under 1R21CA223367, we developed DDMS further (DDMS-2). We tested the ability of the DDMS-2 assay to distinguish benign from malignant surgically excised thyroid nodules (n=121). In this Pilot study, DDMS- 2 had an estimated positive predictive value (PPV) of 96% and a negative predictive value (NPV) of 98%. Guided by our preliminary data, we hypothesize that DDMS (i) can be successfully used for molecular thyroid cancer diagnostics of pre-operative thyroid nodule aspirations; (ii) will have superior performance in comparison to current thyroid cancer molecular testing and (iii) can affect physician decision-making towards elimination of unnecessary thyroidectomies. We will accomplish our overall objective by pursuing the following specific aims: Aim 1: To perform analytical validation of the DDMS-2 assay. Aim 2: To determine the DDMS-2 accuracy in a prospective cohort obtained from 7 medical centers and containing 1450 thyroid nodule aspirations including 800 aspirations with indeterminate cytopathology. Aim 3: To compare the diagnostic accuracy between DDMS- 2 and two current thyroid cancer molecular diagnostic approaches and to evaluate how the knowledge of the DDMS-2 results impacts clinical management of thyroid nodules. The development of a more accurate assay to distinguish benign and malignant thyroid nodules will address current clinical limitations and reduce the number of needless thyroidectomies and associated morbidities.