Han Patricia Aragon, Kim Hyun-seok, Cho Soonweng, Fazeli Roghayeh, Najafian Alireza, Khawaja Hunain, McAlexander Melissa, Dy Benzon, Sorensen Meredith, Aronova Anna, Sebo Thomas J, Giordano Thomas J, Fahey Thomas J, Thompson Geoffrey B, Gauger Paul G, Somervell Helina, Bishop Justin A, Eshleman James R, Schneider Eric B, Witwer Kenneth W, Umbricht Christopher B, Zeiger Martha A
1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.
2 Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine , Baltimore, Maryland.
Thyroid. 2016 Apr;26(4):532-42. doi: 10.1089/thy.2015.0378. Epub 2016 Mar 7.
Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM).
Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR-221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC.
Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM.
In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers.
研究表明，BRAF（V600E）突变和微小RNA（miR）表达与甲状腺乳头状癌（PTC）侵袭性临床病理特征相关。分析BRAF（V600E）突变与miR表达数据可能有助于改善PTC患者的围手术期决策，特别是在识别有中央淋巴结转移（CLNM）的患者方面。
2012年1月至2013年6月期间，237例连续患者在四个内分泌外科中心接受了全甲状腺切除术和预防性中央淋巴结清扫术（CLND）。对所有肿瘤进行BRAF（V600E）突变以及miR-21、miR-146b-3p、miR-146b-5p、miR-204、miR-221、miR-222和miR-375表达检测。进行双变量和多变量分析以研究分子标志物与PTC侵袭性临床病理特征之间的关联。
对所有临床病理特征进行多变量逻辑回归分析发现，miR-146b-3p和miR-146b-5p是CLNM的独立预测因子，而BRAF（V600E）的存在几乎达到显著水平。仅对术前可用的预测因子（分子标志物、年龄、性别和肿瘤大小）进行多变量逻辑回归分析发现，miR-146b-3p、miR-146b-5p、miR-222和BRAF（V600E）突变可独立预测CLNM。虽然发现BRAF（V600E）与CLNM相关（淋巴结阳性病例中48%发生突变，淋巴结阴性病例中28%发生突变），但其阳性和阴性预测值（分别为48%和72%）限制了其作为单一标志物的临床应用价值。在仅针对接受预防性淋巴结清扫的PTC经典变异型（CVPTC）病例的亚组分析中，多变量逻辑回归分析发现只有miR-146b-5p和miR-222是CLNM的独立预测因子，而BRAF（V600E）与CLNM无显著关联。
在接受预防性CLND的患者中，发现miR-146b-3p、miR-146b-5p和miR-222可在术前预测CLNM。然而，这两种结局组中这些miR的表达存在显著重叠。BRAF（V600E）突变虽然在考虑所有组织学亚型的术前变量时是CLNM的标志物，但在临床上可能不是一个有用的单一标志物，因为淋巴结阳性和阴性病例之间的差异较小。此外，在仅检查CVPTC时它失去了显著性。总体而言，我们的结果说明了分子标志物的统计学意义与实际适用性的概念和解释，引发了关于它们作为个体预后标志物的临床实用性的问题。
