TERT and BRAF in thyroid cancer: teaming up for trouble.

Abstract

TheRomanphilosopherSenecareferstotheideathateveryso-called sin or outcome is the result of a series of complex interconnected factors. This rings true of much of biology, particularly cancer biology. Substantial developments have occurred in the last 5 to 10 years to help us better understand the molecular complexity of thyroid cancer. Among all thyroid cancers, the most common type is papillary thyroid carcinoma (PTC), which comprises approximately 75% of all thyroid cancers. Somatic BRAF mutation was first discovered in thyroid cancer in 2003. Since then, we have learned that BRAF mutation is uniquely seen in PTC and PTC-derived undifferentiated thyroid carcinomas. Prevalence of somatic BRAF mutation in adultonset PTC is approximately 45%, and in PTC-derived undifferentiated thyroid carcinoma, approximately 25%. In subtypes of PTC, the highest percentage of BRAF mutation (77%) is found in the tallcell variant of PTC, and the lowest (12%) in the follicular variant of PTC. In conventional PTC (cPTC), the BRAF mutation is found in approximately 60%. However, BRAF mutation has not been reported in follicular thyroid carcinoma, medullary thyroid carcinoma, thyroid adenoma, or nodular hyperplasia. Results of a multicenter study in PTC showed a strong association of BRAF mutation with lymphnodemetastasis,extrathyroidalextension,advanceddisease(stages III and IV), and disease recurrence. These findings have since been replicated in many independent studies. This knowledge has led to proposed BRAF-stratified surgical and medical management of PTC. In the article that accompanies this editorial, Xing et al extend our current understanding of PTC natural history by demonstrating that coexistence of BRAF p.V600E and TERT c.228C T ( 124C T; previously referred to as C228T) is associated with the worst clinicopathologic characteristics in cPTC as well as PTC subtypes. In previous publications, the authors as well as others had already demonstrated the association of TERT promoter mutations with clinically more aggressive differentiated thyroid cancers. In this study, the authors examined the presence of BRAF p.V600E and TERT 124C T mutations in a large cohort (N 507) of patients with PTC who were treated over a 12-year period at Johns Hopkins Hospital. The median follow-up was 24 months (interquartile range, 8 to 78 months). BRAF and TERT mutations were seen together in 7% of all subtypes of PTC and 7% of cPTC. Tumor recurrences per 1,000 person-years were three-fold greater in patients with either BRAF p.V600E or TERT 124C T mutations, but 8.5-fold if they had both mutations compared with patients with neither mutation. This suggests a synergistic interaction between BRAF and TERT. This is further reflected in the result thatthecoexistenceofbothmutationswasassociatedwithhigh-risk clinicopathologic characteristics, including significantly reduced tumor recurrence-free survival, even after adjusting for other risk factors. MutationsintheTERTpromoterwerefirstreportedinbothfamilial and sporadic melanomas and provided a new mechanism by which cells could acquire increased telomerase activity. There were two highly recurrent somatic mutations ( 124C T [C228T] and 146C T [C250T]) seen in sporadic melanomas, and these mutations have subsequently been associated with other cancers including thyroid, bladder, and glioblastoma. TERT promoter mutations result in twoto four-fold increased promoter activity with the additional unique featurethatthesemutationscreateadenovoCCGGAA/Tgeneralbinding motif for E-26 transcription factors/ternary complex factors (ETS/TCF), which differ from the natural state (ie, wild type) GGAA/T ETS binding site within the TERT promoter. This suggests that upregulation of ETS/ TCF transcription factors will likely enhance TERT activity. The effect of the promoter mutations on TERT expression is only possible in the presence of ETS/TCF transcription factors that bind to the newly created consensus binding site. Some of the ETS/TCF transcription factors are downstream targets of the mitogen-activated protein kinase pathway, where BRAF plays an important role. It is therefore biologically plausible that in both melanoma and thyroid cancer, activated BRAF, by enhancing the effects of TERT promoter mutation, results in poorer outcomes. The study by Xing et al is important because it provides evidence that the coexistence of both mutations is a poor prognostic marker in PTC. This suggests that any molecular-based stratification for treatment or care will need to take both mutations into account and not either BRAF p.V600E or TERT 124C T alone. Although mortality from differentiated thyroid cancer is low, patients deserve to receive the treatment that not only minimizes the likelihood of progression or recurrence, but also has the best risk-benefit and toxicity profiles. Molecular markers could enable clinicians to spare many individuals from invasive surgery and therapies that have many adverse effects. Enrollment of patients with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 25 SEPTEMBER 1 2014