Coexistence of TERT Promoter and BRAF Mutations in Papillary ...

Published Ahead of Print on January 20, 2015 as 10.1200/JCO.2014.59.4614 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.4614

JOURNAL OF CLINICAL ONCOLOGY

Coexistence of TERT Promoter and BRAF Mutations in Papillary Thyroid Carcinoma: Added Value in Patient Prognosis? TO THE EDITOR: We read with interest the study by Xing et al1 recently published in Journal of Clinical Oncology, together with the accompanying editorial.2 In their large series of patients with papillary thyroid carcinoma (PTC) Xing et al observed that the coexistence of TERT promoter ⫺124C⬎T mutation and BRAF V600E mutation is associated with worse clinicopathologic features and increased recurrence rate when compared with the absence of any of such mutations or the presence of just one of them. Xing et al conclude that the coexistence of TERT promoter ⫺124C⬎T and BRAF mutation identifies PTC with the worst clinicopathologic outcomes.1 We think the results of Xing et al1 are relevant and deserve a thoughtful analysis because the data on record on the prognostic meaning of BRAF mutation have not taken into account TERT mutations. Oversimplifying the issue, the question is to clarify whether or not, after controlling the clinical importance of TERT mutations,3 BRAF goes on adding a significant prognostic value. BRAF V600E mutation is the most frequent molecular alteration detected in PTC (45%).4 The association of this mutation with more aggressive clinicopathologic features and worse outcome has been under debate. Being present in about half of the cases of the classical form of PTC and in approximately 40% of papillary microcarcinomas— histotypes carrying in general a good or even an excellent prognosis—most patients with BRAF-mutated tumors usually do well (ie, the positive predictive value of BRAF mutation for worse outcome is low). Among the clinicopathologic features reported to be associated with BRAF mutations, recurrence is one of the most frequently described and has been confirmed in systematic reviews and meta-analysis.4 On the other hand, the association of BRAF V600E mutation with distant metastases is unclear.5 Furthermore, patients with tumors harboring BRAF V600E mutation have increased disease-specific mortality, but this association is dependent on several concurrent clinicopathologic features.6 TERT promoter mutations were recently described in follicular cell– derived thyroid carcinomas.7,8 Both ⫺124C⬎T and ⫺146C⬎T were reported, with overall frequencies ranging between 7.5%27.0%.9 The ⫺124C⬎T is more prevalent than the ⫺146C⬎T, representing the latter 8.5 to 33.9% of the total TERT promoter mutations reported in different studies. Recognizing that the ⫺124C⬎T is more frequent and more potent in vitro,9 we think it is premature to look only for this mutation (as Xing et al did in their study1), since one still ignores the implications of the ⫺146C⬎T mutation in thyroid cancer. In the Xing et al1 series, Journal of Clinical Oncology, Vol 33, 2015

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some of the BRAF positive tumors classified as BRAF alone may indeed be BRAF plus TERT ⫺146C⬎T mutation. Several studies detected an association between TERT mutations and aggressive clinicopathologic features.3,8 The association of TERT promoter mutations with distant metastases, which are known to be a major determinant of patients outcome, is particularly relevant and has been consistently reported in different studies,3,10 including the series of Xing et al.1 In our series3 we found that TERT-mutated tumors were accompanied by significantly higher prevalence of distant metastases and poorer survival, regardless of the BRAF status. At variance with the comparison regarding recurrence rate, Xing et al have not compared TERTmutated tumors alone versus TERT- plus BRAF-mutated tumors regarding distant metastases. We think that the groups of patients with tumors harboring TERT promoter mutations with and without BRAF V600E should be the ones to be compared regarding clinicopathologic features including distant metastases and outcome. This would be the way to find whether or not adding BRAF status to TERT-mutated tumors could have significant prognostic implications. In our previous study,3 we compared cases harboring TERT promoter mutations with or without BRAF V600E and we did not find any difference regarding clinicopathologic features or disease-specific mortality, although we realize that the number of patients included in our subgroups is too limited to draw a definitive conclusion. In summary, we think there is enough evidence to state that TERT promoter mutations are a major indicator of poor prognosis in differentiated thyroid cancer and notably in PTC, due to its association with distant metastasization and increased diseasespecific mortality.3 To find if the addition of BRAF status has prognostic implications in TERT promoter–mutated PTC, large multicentric studies are necessary in which both ⫺124C⬎T and ⫺146C⬎T mutations are analyzed and the groups of patients with TERT-mutated tumors with and without BRAF mutation are compared regarding their clinicopathologic features and outcome. Even if the prognostic value of the BRAF mutation is not confirmed in this setting, its detection may go on being necessary for diagnostic and/or therapeutic purposes.

Miguel Melo Institute of Molecular Pathology and Immunology; University of Porto, Porto; University and Hospital Center of Coimbra; University of Coimbra, Coimbra, Portugal

Adriana Gaspar da Rocha Institute of Molecular Pathology and Immunology; University of Porto, Porto, Portugal

João Vinagre Institute of Molecular Pathology and Immunology; Institute of Biomedical Sciences of Abel Salazar, University of Porto, Porto, Portugal

Manuel Sobrinho-Simões Institute of Molecular Pathology and Immunology; University of Porto; Hospital S. João, Porto, Portugal

© 2015 by American Society of Clinical Oncology

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Copyright 2015 by American Society of Clinical Oncology

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Correspondence

Paula Soares Institute of Molecular Pathology and Immunology; University of Porto, Porto, Portugal

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org. REFERENCES 1. Xing M, Liu R, Liu X, et al: BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 32:2718-2726, 2014 2. Ngeow J, Eng C: TERT and BRAF in thyroid cancer: Teaming up for trouble. J Clin Oncol 32:2683-2684, 2014 3. Melo M, da Rocha AG, Vinagre J, et al: TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 99:E754-E765, 2014 4. Xing M: Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 321:86-93, 2010

5. Sancisi V, Nicoli D, Ragazzi M, et al: BRAFV600E mutation does not mean distant metastasis in thyroid papillary carcinomas. J Clin Endocrinol Metab 97:E1745-E1749, 2012 6. Xing M, Alzahrani AS, Carson KA, et al: Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:14931501, 2013 7. Vinagre J, Almeida A, Populo H, et al: Frequency of TERT promoter mutations in human cancers. Nat Commun 4:2185, 2013 8. Liu X, Bishop J, Shan Y, et al: Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer 20:603-610, 2013 9. Vinagre J, Pinto V, Celestino R, et al: Telomerase promoter mutations in cancer: An emerging molecular biomarker? Virchows Arch 465:119-133, 2014 10. Liu T, Wang N, Cao J, et al: The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 33: 4978-4984, 2013

DOI: 10.1200/JCO.2014.59.4614; published online ahead of print at www.jco.org on January 20, 2015

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JOURNAL OF CLINICAL ONCOLOGY


Correspondence

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Coexistence of TERT Promoter and BRAF Mutations in Papillary Thyroid Carcinoma: Added Value in Patient Prognosis? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Miguel Melo Honoraria: Bial Consulting or Advisory Role: Bial Speakers’ Bureau: Bial, Novo Nordisk, Genzyme Research Funding: Genzyme Travel, Accommodations, Expenses: Novo Nordisk, Genzyme Adriana Gaspar da Rocha No relationship to disclose

Manuel Sobrinho-Simões Other Relationship: Janssen Oncology Paula Soares Patents, Royalties, Other Intellectual Property: Patent pending, method for the detection of the mutations ⫺124C⬎ T and ⫺146C⬎ T in the gene HTERT

João Vinagre Patents, Royalties, Other Intellectual Property: Patent pending, method for the detection of the mutations ⫺124C⬎T and ⫺146C⬎ T in the gene HTERT

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