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Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers.
Thyroid. 2016 Apr; 26(4):532-42.T

Abstract

BACKGROUND

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).

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 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.

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 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.

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 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.

Authors+Show Affiliations

1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.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.3 Departments of Surgery, Mayo Clinic , Rochester, Minnesota.4 Division of Endocrine Surgery, University of Michigan Health System , Ann Arbor, Michigan.5 Endocrine Surgery Section, Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center , New York, New York.6 Laboratory Medicine and Pathology, Mayo Clinic , Rochester, Minnesota.7 Departments of Pathology and Internal Medicine, University of Michigan Health System , Ann Arbor, Michigan.5 Endocrine Surgery Section, Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center , New York, New York.3 Departments of Surgery, Mayo Clinic , Rochester, Minnesota.4 Division of Endocrine Surgery, University of Michigan Health System , Ann Arbor, Michigan.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.8 Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, Maryland.8 Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, Maryland.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.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

26950846

Citation

Han, Patricia Aragon, et al. "Association of BRAF V600E Mutation and MicroRNA Expression With Central Lymph Node Metastases in Papillary Thyroid Cancer: a Prospective Study From Four Endocrine Surgery Centers." Thyroid : Official Journal of the American Thyroid Association, vol. 26, no. 4, 2016, pp. 532-42.
Han PA, Kim HS, Cho S, et al. Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers. Thyroid. 2016;26(4):532-42.
Han, P. A., Kim, H. S., Cho, S., Fazeli, R., Najafian, A., Khawaja, H., McAlexander, M., Dy, B., Sorensen, M., Aronova, A., Sebo, T. J., Giordano, T. J., Fahey, T. J., Thompson, G. B., Gauger, P. G., Somervell, H., Bishop, J. A., Eshleman, J. R., Schneider, E. B., ... Zeiger, M. A. (2016). Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers. Thyroid : Official Journal of the American Thyroid Association, 26(4), 532-42. https://doi.org/10.1089/thy.2015.0378
Han PA, et al. Association of BRAF V600E Mutation and MicroRNA Expression With Central Lymph Node Metastases in Papillary Thyroid Cancer: a Prospective Study From Four Endocrine Surgery Centers. Thyroid. 2016;26(4):532-42. PubMed PMID: 26950846.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers. AU - Han,Patricia Aragon, 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,3rd 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, Y1 - 2016/03/07/ PY - 2016/3/8/entrez PY - 2016/3/8/pubmed PY - 2017/3/18/medline SP - 532 EP - 42 JF - Thyroid : official journal of the American Thyroid Association JO - Thyroid VL - 26 IS - 4 N2 - BACKGROUND: 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). 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 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. 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 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. 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 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. SN - 1557-9077 UR - https://www.unboundmedicine.com/medline/citation/26950846/Association_of_BRAF_V600E_Mutation_and_MicroRNA_Expression_with_Central_Lymph_Node_Metastases_in_Papillary_Thyroid_Cancer:_A_Prospective_Study_from_Four_Endocrine_Surgery_Centers_ L2 - https://www.liebertpub.com/doi/full/10.1089/thy.2015.0378?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -