Jonathan R George1, Ying C Henderson1, Michelle D Williams1, Dianna B Roberts1, Hu Hei1, Stephen Y Lai1, Gary L Clayman1. 1. Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Abstract
CONTEXT: Papillary thyroid carcinoma (PTC) carrying the BRAF mutation has been reported to be associated with high recurrence and potentially increased mortality. PTC carrying the TERT promoter mutation has been associated with older age, recurrence, and aggressive disease. OBJECTIVE: The objective of this study was to determine the association of BRAF and TERT promoter gene alterations with recurrence and survival in a high-risk population. DESIGN: Genomic DNA was analyzed for the BRAF mutation from 256 persistent/recurrent PTC (p/rPTC; 202 new, 54 previously reported) and for the TERT promoter mutation and polymorphism (242 p/rPTC). Two-tailed Fisher exact tests or the Pearson χ(2) test were performed for the associations between mutations and other variables. Overall and disease-free survivals were compared by log rank tests on Kaplan-Meier plots and by Cox regression analysis. TERT promoter constructs were tested in PTC cell lines to determine their activities in these cells. RESULTS: BRAF V600E mutation was identified in 235 of 256 (91.8%), TERT promoter mutation at -124 was detected in 77 of 242 (31.8%), and TERT promoter polymorphism at -245 was found in 113 of 242 (46.7%) p/rPTC patients. A significant difference in survival was found in p/rPTC patients with the TERT promoter mutation, which also displayed increased activity in vitro as compared to the nonmutated promoter sequence. No association was noted between the BRAF mutation or TERT promoter polymorphism and recurrence or survival. A drawback of our study could be the limited number of patients with nonmutated BRAF (21 of 256 [8.2%]). CONCLUSIONS: Mutation in the TERT promoter, but not in BRAF, was associated with decreased survival in 19 (24.7%) p/rPTC patients who died of disease and in 38 (49.4%) p/rPTC patients who died at last contact. The presence or absence of the BRAF mutation and TERT promoter polymorphism, however, was not significantly correlated with survival.
CONTEXT: Papillary thyroid carcinoma (PTC) carrying the BRAF mutation has been reported to be associated with high recurrence and potentially increased mortality. PTC carrying the TERT promoter mutation has been associated with older age, recurrence, and aggressive disease. OBJECTIVE: The objective of this study was to determine the association of BRAF and TERT promoter gene alterations with recurrence and survival in a high-risk population. DESIGN: Genomic DNA was analyzed for the BRAF mutation from 256 persistent/recurrent PTC (p/rPTC; 202 new, 54 previously reported) and for the TERT promoter mutation and polymorphism (242 p/rPTC). Two-tailed Fisher exact tests or the Pearson χ(2) test were performed for the associations between mutations and other variables. Overall and disease-free survivals were compared by log rank tests on Kaplan-Meier plots and by Cox regression analysis. TERT promoter constructs were tested in PTC cell lines to determine their activities in these cells. RESULTS:BRAFV600E mutation was identified in 235 of 256 (91.8%), TERT promoter mutation at -124 was detected in 77 of 242 (31.8%), and TERT promoter polymorphism at -245 was found in 113 of 242 (46.7%) p/rPTC patients. A significant difference in survival was found in p/rPTC patients with the TERT promoter mutation, which also displayed increased activity in vitro as compared to the nonmutated promoter sequence. No association was noted between the BRAF mutation or TERT promoter polymorphism and recurrence or survival. A drawback of our study could be the limited number of patients with nonmutated BRAF (21 of 256 [8.2%]). CONCLUSIONS: Mutation in the TERT promoter, but not in BRAF, was associated with decreased survival in 19 (24.7%) p/rPTC patients who died of disease and in 38 (49.4%) p/rPTC patients who died at last contact. The presence or absence of the BRAF mutation and TERT promoter polymorphism, however, was not significantly correlated with survival.
Authors: P Sivaramakrishna Rachakonda; Ismail Hosen; Petra J de Verdier; Mahdi Fallah; Barbara Heidenreich; Charlotta Ryk; N Peter Wiklund; Gunnar Steineck; Dirk Schadendorf; Kari Hemminki; Rajiv Kumar Journal: Proc Natl Acad Sci U S A Date: 2013-10-07 Impact factor: 11.205
Authors: Christopher Gouveia; Nhu Thuy Can; Alan Bostrom; James P Grenert; Annemieke van Zante; Lisa A Orloff Journal: JAMA Otolaryngol Head Neck Surg Date: 2013-11 Impact factor: 6.223
Authors: Mingzhao Xing; Ali S Alzahrani; Kathryn A Carson; David Viola; Rossella Elisei; Bela Bendlova; Linwah Yip; Caterina Mian; Federica Vianello; R Michael Tuttle; Eyal Robenshtok; James A Fagin; Efisio Puxeddu; Laura Fugazzola; Agnieszka Czarniecka; Barbara Jarzab; Christine J O'Neill; Mark S Sywak; Alfred K Lam; Garcilaso Riesco-Eizaguirre; Pilar Santisteban; Hirotaka Nakayama; Ralph P Tufano; Sara I Pai; Martha A Zeiger; William H Westra; Douglas P Clark; Roderick Clifton-Bligh; David Sidransky; Paul W Ladenson; Vlasta Sykorova Journal: JAMA Date: 2013-04-10 Impact factor: 56.272
Authors: Miguel Melo; Adriana Gaspar da Rocha; João Vinagre; Rui Batista; Joana Peixoto; Catarina Tavares; Ricardo Celestino; Ana Almeida; Catarina Salgado; Catarina Eloy; Patrícia Castro; Hugo Prazeres; Jorge Lima; Teresina Amaro; Cláudia Lobo; Maria João Martins; Margarida Moura; Branca Cavaco; Valeriano Leite; José Manuel Cameselle-Teijeiro; Francisco Carrilho; Manuela Carvalheiro; Valdemar Máximo; Manuel Sobrinho-Simões; Paula Soares Journal: J Clin Endocrinol Metab Date: 2014-01-29 Impact factor: 5.958
Authors: Sarika N Rao; Mark Zafereo; Ramona Dadu; Naifa L Busaidy; Kenneth Hess; Gilbert J Cote; Michelle D Williams; William N William; Vlad Sandulache; Neil Gross; G Brandon Gunn; Charles Lu; Renata Ferrarotto; Stephen Y Lai; Maria E Cabanillas Journal: Thyroid Date: 2017-02-16 Impact factor: 6.568
Authors: Gustavo C Penna; Ana Pestana; José Manuel Cameselle; Denise Momesso; Fernanda Accioly de Andrade; Ana Paula Aguiar Vidal; Mario Lucio Araujo Junior; Miguel Melo; Priscila Valverde Fernandes; Rossana Corbo; Mario Vaisman; Manuel Sobrinho-Simões; Paula Soares; Fernanda Vaisman Journal: Endocrine Date: 2018-06-15 Impact factor: 3.633
Authors: Pablo Tamayo; Thomas R Cech; Franklin W Huang; Josh Lewis Stern; Grace Hibshman; Kevin Hu; Sarah E Ferrara; James C Costello; William Kim Journal: Mol Cancer Res Date: 2020-04-10 Impact factor: 5.852
Authors: Robert J A Bell; H Tomas Rube; Ana Xavier-Magalhães; Bruno M Costa; Andrew Mancini; Jun S Song; Joseph F Costello Journal: Mol Cancer Res Date: 2016-03-03 Impact factor: 5.852