Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, 1 Ford Place, 1D-06, Detroit, MI, 48202, USA.
Department of Pathology, Henry Ford Hospital, Detroit, MI, 48202, USA.
J Endocrinol Invest. 2018 Feb;41(2):163-170. doi: 10.1007/s40618-017-0702-2. Epub 2017 Jun 13.
The incidence of thyroid cancer (TC) is increasing. Cytology by itself cannot distinguish TC from some benign nodules especially in certain subtypes of TC. Our immediate goal is to identify DNA methylation markers for early detection of TC and to molecularly differentiate TC subtypes from benign nodules.
Promoter methylation status of 21 candidate genes was examined on formalin-fixed paraffin-embedded tissue (FFPE) utilizing quantitative methylation-specific polymerase chain reaction (QMSP) in a retrospective cohort of 329 patients (56% white, 29% African American, 61% female) comprising 71 normal thyroid, 83 benign nodules [follicular adenomas (FA)], 90 follicular TC (FTC) and 85 papillary TC (PTC). All genes were analyzed individually (Kruskal-Wallis and Wilcoxon rank sum tests) and in combination (logistic regression models) to identify genes whose methylation levels might best separate groups.
Combination gene panels TPO and UCHL1 (ROC = 0.607, sensitivity 78%) discriminated FTC from FA, and RASSF1 and TPO (ROC = 0.881, sensitivity 78%) discriminated FTC from normal. Methylation of TSHR distinguished PTC from FTC (ROC = 0.701, sensitivity 84%) and PTC from FA (ROC = 0.685, sensitivity 70%). The six gene panel of TIMP3, RARB2, SERPINB5, RASSF1, TPO and TSHR, which differentiates PTC from normal thyroid, had the best combination sensitivity (91%) and specificity (81%) of the panels addressing discrimination of cancer tissue.
Aberrant gene methylation used in combination panels may be useful clinically in differentiating FTC and PTC from benign nodules. If confirmed in additional studies, these findings could help reduce the over diagnosis of thyroid cancer and surgeries related to over diagnosis.
甲状腺癌 (TC) 的发病率正在上升。细胞学本身无法区分 TC 与某些良性结节，尤其是在某些 TC 亚型中。我们的直接目标是确定用于 TC 早期检测的 DNA 甲基化标记，并从良性结节中对 TC 亚型进行分子区分。
利用定量甲基化特异性聚合酶链反应 (QMSP) 在一个由 329 名患者（56%为白人，29%为非裔美国人，61%为女性）组成的回顾性队列中，对 21 个候选基因的启动子甲基化状态进行了检查，这些患者包括 71 例正常甲状腺、83 例良性结节[滤泡性腺瘤 (FA)]、90 例滤泡状 TC (FTC) 和 85 例乳头状 TC (PTC)。所有基因均单独进行分析（Kruskal-Wallis 和 Wilcoxon 秩和检验）和组合分析（逻辑回归模型），以确定最能区分组别的甲基化水平的基因。
TPO 和 UCHL1 组合基因谱（ROC=0.607，敏感性 78%）可区分 FTC 与 FA，RASSF1 和 TPO 组合基因谱（ROC=0.881，敏感性 78%）可区分 FTC 与正常。TSHR 的甲基化可将 PTC 与 FTC（ROC=0.701，敏感性 84%）和 PTC 与 FA（ROC=0.685，敏感性 70%）区分开来。TIMP3、RARB2、SERPINB5、RASSF1、TPO 和 TSHR 的六基因谱，可将 PTC 与正常甲状腺区分开来，该谱在区分癌症组织方面具有最佳的组合敏感性（91%）和特异性（81%）。
联合基因谱中异常的基因甲基化可能在临床上有助于区分 FTC 和 PTC 与良性结节。如果在进一步的研究中得到证实，这些发现可能有助于减少甲状腺癌的过度诊断和与过度诊断相关的手术。
