Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers

Patricia Aragon Han, Hyun Seok Kim, Soonweng Cho, Roghayeh Fazeli, Alireza Najafian, Hunain Khawaja, Melissa McAlexander, Benzon Dy, Meredith Sorensen, Anna Aronova, Thomas J. Sebo, Thomas J. Giordano, Thomas J. Fahey, Geoffrey B. Thompson, Paul G. Gauger, Helina Somervell, Justin A. Bishop, James R. Eshleman, Eric B. Schneider, Kenneth W. WitwerChristopher B. Umbricht, Martha A. Zeiger

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Studies have demonstrated an association of the BRAFV600E mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAFV600E mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). Methods: 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 BRAFV600E 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. Results: 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 BRAFV600E 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 BRAFV600E mutation to predict CLNM independently. While BRAFV600E 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 BRAFV600E was not significantly associated with CLNM. Conclusion: 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 BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)532-542
Number of pages11
JournalThyroid
Volume26
Issue number4
DOIs
StatePublished - Apr 1 2016

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MicroRNAs
Lymph Nodes
Prospective Studies
Neoplasm Metastasis
Mutation
Papillary Thyroid cancer
Logistic Models
Regression Analysis
Lymph Node Excision
Factor IX
Thyroidectomy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer : A Prospective Study from Four Endocrine Surgery Centers. / Aragon Han, Patricia; 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.

In: Thyroid, Vol. 26, No. 4, 01.04.2016, p. 532-542.

Research output: Contribution to journalArticle

Aragon Han, P, Kim, HS, Cho, S, Fazeli, R, Najafian, A, Khawaja, H, McAlexander, M, Dy, B, Sorensen, M, Aronova, A, Sebo, TJ, Giordano, TJ, Fahey, TJ, Thompson, GB, Gauger, PG, Somervell, H, Bishop, JA, Eshleman, JR, Schneider, EB, Witwer, KW, Umbricht, CB & Zeiger, MA 2016, 'Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers', Thyroid, vol. 26, no. 4, pp. 532-542. https://doi.org/10.1089/thy.2015.0378
Aragon Han, Patricia ; 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. / Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer : A Prospective Study from Four Endocrine Surgery Centers. In: Thyroid. 2016 ; Vol. 26, No. 4. pp. 532-542.
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title = "Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers",
abstract = "Background: Studies have demonstrated an association of the BRAFV600E mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAFV600E mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). Methods: 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 BRAFV600E 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. Results: 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 BRAFV600E 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 BRAFV600E mutation to predict CLNM independently. While BRAFV600E 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 BRAFV600E was not significantly associated with CLNM. Conclusion: 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 BRAFV600E 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.",
author = "{Aragon Han}, Patricia and Kim, {Hyun Seok} and Soonweng Cho and Roghayeh Fazeli and Alireza Najafian and Hunain Khawaja and Melissa McAlexander and Benzon Dy and Meredith Sorensen and Anna Aronova and Sebo, {Thomas J.} and Giordano, {Thomas J.} and Fahey, {Thomas J.} and Thompson, {Geoffrey B.} and Gauger, {Paul G.} and Helina Somervell and Bishop, {Justin A.} and Eshleman, {James R.} and Schneider, {Eric B.} and Witwer, {Kenneth W.} and Umbricht, {Christopher B.} and Zeiger, {Martha A.}",
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TY - JOUR

T1 - Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer

T2 - A Prospective Study from Four Endocrine Surgery Centers

AU - Aragon Han, Patricia

AU - Kim, Hyun Seok

AU - Cho, Soonweng

AU - Fazeli, Roghayeh

AU - Najafian, Alireza

AU - Khawaja, Hunain

AU - McAlexander, Melissa

AU - Dy, Benzon

AU - Sorensen, Meredith

AU - Aronova, Anna

AU - Sebo, Thomas J.

AU - Giordano, Thomas J.

AU - Fahey, Thomas J.

AU - Thompson, Geoffrey B.

AU - Gauger, Paul G.

AU - Somervell, Helina

AU - Bishop, Justin A.

AU - Eshleman, James R.

AU - Schneider, Eric B.

AU - Witwer, Kenneth W.

AU - Umbricht, Christopher B.

AU - Zeiger, Martha A.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Background: Studies have demonstrated an association of the BRAFV600E mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAFV600E mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). Methods: 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 BRAFV600E 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. Results: 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 BRAFV600E 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 BRAFV600E mutation to predict CLNM independently. While BRAFV600E 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 BRAFV600E was not significantly associated with CLNM. Conclusion: 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 BRAFV600E 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.

AB - Background: Studies have demonstrated an association of the BRAFV600E mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAFV600E mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). Methods: 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 BRAFV600E 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. Results: 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 BRAFV600E 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 BRAFV600E mutation to predict CLNM independently. While BRAFV600E 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 BRAFV600E was not significantly associated with CLNM. Conclusion: 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 BRAFV600E 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.

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