Coexisting RET/PTC and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targets in Thyroid Cancer.

PURPOSE: To investigate the role of coexisting RET/PTC rearrangement and TERT promoter mutation in the prognosis and therapeutic targeting in papillary thyroid cancer (PTC). METHODS: A total of 669 PTC patients with complete clinical follow-up and genetic data were pooled from thyroid cancer datasets TCGA, MSK MetTropism, and MSK-IMPACT, from whom 163 patients (112 women and 47 men, 4 unknown) with wild-type BRAF/RAS were identified, with median age (IQR) of 46.00 (33.00, 61.00) years and median follow-up time (IQR) of 16.13 (8.09, 27.91) months for comparative genotype cohort analysis of mortality. RESULTS: There was a significant concurrence index between RET/PTC and TERT promoter mutations, being 2.040 (95% CI 1.110-3.747, P = 0.023). Mortality occurred in 5/100 (5%) patients harboring neither mutation, 2/18 (11.1%) patients harboring TERT promoter mutation alone, 0/31 (0%) patients harboring RET/PTC alone, and 7/14 (50%) patients harboring both genetic alterations, corresponding to HRs (95% CI) of 1 (Reference), 2.469 (0.405-14.02), 3.296e-09 (0-inf), and 9.019 (2.635-30.87), respectively, which remained essentially unchanged after adjustment for patient race, sex, and age. Similar results were observed with BRAF/RAS and TERT promoter mutations. Mechanistically, RET/PTC used the MAP kinase pathway to upregulate the mutated TERT, but not the wild-type TERT, and, correspondingly, targeting RET and MEK could suppress mutated TERT but not the wild-type TERT. CONCLUSION: Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.

Association Between a History of Breast Cancer and Decreased Thyroid Cancer-specific Mortality.

CONTEXT: The clinical relevance of the well-known association between thyroid cancer (TC) and breast cancer (BC) remains to be further defined. OBJECTIVE: This work aimed to investigate the effect of history of BC on the prognosis of TC. METHODS: This was a comparative cohort study of tumor behaviors and TC-specific mortality in 5598 patients with papillary thyroid cancer (PTC) and 604 patients with follicular thyroid cancer (FTC), all with a history of BC (TC-BC patients), and their propensity score-matched TC patients without a history of BC (TCnoBC patients) in Surveillance, Epidemiology and End Results (SEER) 18. The main outcome measure was TC-specific mortality. RESULTS: Lower TC distant metastasis rates of 2.4% vs 3.0% in PTC and 6.1% vs 9.1% in FTC and TC-specific mortality rates of 1.3% vs 2.6% in PTC and 5.8% vs 8.4% in FTC were found in TC-BC patients vs matched TCnoBC patients (all P < .05). Comparing TC-BC patients with matched TCnoBC patients, hazard ratios (HRs) for mortality were 0.472 (95% CI, 0.370-0.601) in PTC and 0.656 (95% CI, 0.461-0.934) in FTC (all P < .05). Such HRs for mortality in PTC were 0.397 (95% CI, 0.268-0.588; P < .001) when TC occurred before BC vs 0.607 (95% CI, 0.445-0.827; P = .002) when BC occurred before TC. CONCLUSION: This study demonstrates a robust protective effect of a history of BC on TC-specific patient survival, which has strong implications for more precise prognostication of TC in such patients.

Genetic trio of BRAF and TERT alterations and rs2853669TT in papillary thyroid cancer aggressiveness.

BACKGROUND: BRAF V600E and TERT promoter alterations are core components in current genetics-based risk assessment for precision management of papillary thyroid cancer. It remains unknown whether this approach could achieve even better precision through a widely recognized prognostic single-nucleotide variation (SNV, formerly SNP), rs2853669T>C, in the TERT promoter. METHODS: The genetic status of alterations and SNV were examined by sequencing genomic DNA from papillary thyroid cancer in 608 patients (427 women and 181 men) aged 47 years (interquartile range = 37-57), with a median follow-up time of 75 months (interquartile range = 36-123), and their relationship with clinical outcomes was analyzed. A luciferase reporter assay was performed to examine TERT promoter activities. RESULTS: TERT promoter alterations showed a strong association with papillary thyroid cancer recurrence in the presence of genotype TT of rs2853669 (adjusted hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.10 to 4.12) but not TC/CC (adjusted HR = 1.17, 95% CI = 0.56 to 2.41). TERT and BRAF alterations commonly coexisted and synergistically promoted papillary thyroid cancer recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence than TC/CC (adjusted HR = 14.26, 95% CI = 2.86 to 71.25). Patients with the genetic trio of BRAF V600E, TERT alteration, and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither variation and with TC/CC (HR = 13.48, 95% CI = 6.44 to 28.21). T allele of rs2853669 strongly increased TERT promoter activities, particularly the variant promoters. CONCLUSIONS: The SNV rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter alterations to a higher precision, suggesting the need for including this SNV in the current genetics-based risk prognostication of papillary thyroid cancer.

Hypoxia switches TET1 from being tumor-suppressive to oncogenic.

The classical oxidizing enzymatic activity of Ten Eleven Translocation 1 (TET1) and its tumor suppressor role are well known. Here, we find that high TET1 expression is associated with poor patient survival in solid cancers often having hypoxia, which is inconsistent with its tumor suppressor role. Through a series of in vitro and in vivo studies, using thyroid cancer as a model, we demonstrate that TET1 plays a tumor suppressor function in normoxia and, surprisingly, an oncogenic function in hypoxia. Mechanistically, TET1 mediates HIF1α-p300 interaction by acting as a co-activator of HIF1α to promote CK2B transcription under hypoxia, which is independent of its enzymatic activity; CK2 activates the AKT/GSK3ß signaling pathway to promote oncogenesis. Activated AKT/GSK3ß signaling in turn maintains HIF1α at elevated levels by preventing its K48-linked ubiquitination and degradation, creating a feedback loop to enhance the oncogenicity of TET1 in hypoxia. Thus, this study uncovers a novel oncogenic mechanism in which TET1 promotes oncogenesis and cancer progression through a non-enzymatic interaction between TET1 and HIF1α in hypoxia, providing novel therapeutic targeting implications for cancer.

High Diagnostic Accuracy of Epigenetic Imprinting Biomarkers in Thyroid Nodules.

PURPOSE: To explore the novel diagnostic value of epigenetic imprinting biomarkers in thyroid nodules. PATIENTS AND METHODS: A total of 550 patients with fine-needle aspiration (FNA)-evaluated and histopathologically confirmed thyroid nodules were consecutively recruited from eight medical centers. Quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) was used to assess the allelic expression of imprinted genes SNRPN and HM13, on the basis of which a diagnostic grading model for thyroid nodules was developed. The model was retrospectively trained on 124 postsurgical thyroid samples, optimized on 32 presurgical FNA samples, and prospectively validated on 394 presurgical FNA samples. Blinded central review-based cytopathologic and histopathologic diagnoses were used as the reference standard. RESULTS: For thyroid malignancy, the QCIGISH test achieved an overall diagnostic sensitivity of 100% (277/277), a specificity of 91.5% (107/117; 95% CI, 86.4 to 96.5), a positive predictive value (PPV) of 96.5% (95% CI, 94.4 to 98.6), and a negative predictive value (NPV) of 100% in the prospective validation, with a diagnostic accuracy of 97.5% (384/394; 95% CI, 95.9 to 99.0). QCIGISH demonstrated a PPV of 97.8% (95% CI, 94.7 to 100) and NPV of 100%, with a diagnostic accuracy of 98.2% (111/113; 95% CI, 95.8 to 100), for indeterminate Bethesda III-V thyroid nodules. QCIGISH demonstrated a PPV of 96.6% (95% CI, 91.9 to 100) and a NPV of 100%, with a diagnostic accuracy of 97.5% (79/81; 95% CI, 94.2 to 100), for Bethesda III-IV. For Bethesda VI, QCIGISH showed a 100% (184/184) accuracy. CONCLUSION: This imprinting biomarker-based test can effectively distinguish malignant from benign thyroid nodules. The high PPV and NPV make the test both an excellent rule-in and rule-out diagnostic tool. With such a diagnostic performance and its technical simplicity, this novel thyroid molecular test is clinically widely applicable.

BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer.

CONTEXT: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. OBJECTIVE: To study whether BRAF V600E affected LNM-associated mortality in PTC. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. RESULTS: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. CONCLUSIONS: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2.

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.

TERT promoter mutation determines apoptotic and therapeutic responses of BRAF-mutant cancers to BRAF and MEK inhibitors: Achilles Heel.

Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.

The Genetic Duet of BRAF V600E and TERT Promoter Mutations Robustly Predicts Loss of Radioiodine Avidity in Recurrent Papillary Thyroid Cancer.

BRAF V600E and TERT promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes. This study investigated the role of mutation patterns in loss of RAI avidity in recurrent PTC. Methods: This was a retrospective study of the relationship between loss of RAI avidity in structural recurrent PTC and the genotype patterns of BRAF V600E and TERT promoter mutations in 164 patients (104 women and 60 men) with a median age of 50 y (interquartile range, 35-62 y). Results: The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When the cohort was divided into mutation and wild-type groups, the RAI avidity loss was 80.4% versus 33.9% (P < 0.001) in BRAF V600E versus wild-type BRAF patients, with an adjusted odds ratio of 7.11 (95% confidence interval [CI], 3.24-16.27), and 89.4% versus 52.1% (P < 0.001) in TERT mutation versus wild-type patients, with an adjusted odds ratio of 6.89 (95% CI, 2.28-25.66). When the cohort was divided into 4 genotypes, the RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with BRAF V600E alone, TERT mutation alone, and the genetic duet of coexisting BRAF and TERT mutations, versus 30.2% (16/53) in patients with neither mutation (P < 0.001, = 0.251, and < 0.001, respectively). These corresponded to odds ratios of 5.39 (95% CI, 2.31-13.13), 2.84 (95% CI, 0.53-16.32), and 81.04 (95% CI, 11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; P = 0.019) between BRAF V600E and TERT mutation in cooperatively affecting RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. Conclusion:BRAF V600E alone and, particularly, coexisting BRAF V600E and TERT promoter mutations are strongly associated with loss of RAI avidity and impairment of the iodide-metabolizing machinery in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC.

BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma.

INTRODUCTION: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management. METHODS: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months). RESULTS: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC. CONCLUSIONS: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.

Correction: Decreased breast cancer-specific mortality risk in patients with a history of thyroid cancer.

[This corrects the article DOI: 10.1371/journal.pone.0221093.].

Decreased breast cancer-specific mortality risk in patients with a history of thyroid cancer.

Previous studies have documented an intrinsic association between breast cancer (BC) and thyroid cancer (TC), but the clinical relevance of this relationship is not well defined. In the present study, we specifically investigated the impact of a history of TC on clinical outcomes of BC. We performed a population-based comparative analysis of tumor behaviors and BC-specific mortalities in 427,893 female patients with BC in the USA Surveillance, Epidemiology and End Results 9 database (1973-2013). In this cohort of subjects, 2,569 patients also had a history of differentiated TC (BC/TC), including BC diagnosed before TC (BC-1st) and BC diagnosed after TC (TC-1st), with the median follow-up time of 81 (IQR, 33-160) months. We found that, compared with matched BC-only patients, less aggressive BC tumor behaviors occurred in BC/TC patients, as exemplified by a distant metastasis rate of 7.0% in the former versus 3.3% in the latter (P<0.001). In BC/TC, BC-1st, and TC-1st patients versus their matched BC-only patients, BC-specific mortalities were 11.3% versus 21.0%, 9.9% versus 26.4%, and 12.4% versus 16.9%. These corresponded to hazard ratios (HR) (95% CI) of 0.47 (0.42-0.53), 0.31 (0.26-0.37), and 0.72 (0.61-0.84), respectively (all P<0.001), being lowest in BC-1st patients <50 years old [HR = 0.22 (0.16-0.31)], which remained significant after adjustment for clinicopathological and socioeconomic factors. Estrogen/progesterone receptor expression in BC tumors was significantly higher in patients with BC/TC than matched BC-only patients, providing evidence that BC in the former was biologically unique. Thus, a history of TC, particularly in younger BC-1st patients, may identify BC as a unique disease entity characterized by a decreased disease-specific mortality risk. The results have potentially important clinical and biological implications for BC in this special patient population and encourage further studies to confirm.

Stage II Differentiated Thyroid Cancer Is a High-Risk Disease in Patients <45/55 Years Old.

PURPOSE: The mortality risk of stage II differentiated thyroid cancer (DTC) based on the American Joint Committee on Cancer (AJCC) staging system requires further investigation. METHODS: Retrospective study of DTC in the US Surveillance, Epidemiology, and End Results program for disease-specific mortality risk in various AJCC stages, with patient age stratification of stage II disease. RESULTS: Using AJCC staging system 6.0, hazard ratios (HRs) of mortality for stage II DTC in patients <45 yo and patients ≥45 yo and stages III, IVA, IVB, and IVC compared with stage I were 46.95, 4.95, 9.82, 57.37, 222.10, and 468.68, respectively, showing a robustly higher mortality risk in stage II disease in patients <45 yo than in older patients (P < 0.001), comparable with stage IVA (P = 0.482). Similar results were obtained with AJCC 7.0. With AJCC 8.0, HRs of mortality for stage II in patients <55 yo and patients ≥55 yo and stages III, IVA, and IVB compared with stage I were 75.16, 11.23, 69.45, 134.94, and 235.70, respectively, showing a robustly higher risk in stage II disease in patients <55 yo than in older patients (P < 0.001), comparable with stage III (P = 0.57). Kaplan-Meier survival curves displayed a sharp decline with stage II disease in patients <45/55 yo compared with older patients. CONCLUSIONS: The mortality risk of stage II DTC was sharply differentiated at patient age 45/55 years, being robustly high in younger patients and comparable with stage III/IVA. This emphasizes the importance of considering age when managing stage II DTC and not treating it as a uniformly low-risk disease.

Identification and characterization of two novel oncogenic mTOR mutations.

Mammalian target of rapamycin (mTOR) signaling is often aberrantly activated, particularly when genetically altered, in human cancers. mTOR inhibitors targeting the activated mTOR signaling are highly promising anti-cancer drugs. Knowing the activating genetic change in mTOR can help guide the use of mTOR inhibitors for cancer treatment. This study was conducted to identify and characterize novel oncogenic mTOR mutations that can potentially be therapeutic targets in human cancer. We sequenced 30 exons of the mTOR gene in 12 thyroid cancer cell lines, 3 melanoma cell lines, 20 anaplastic thyroid cancer (ATC) tumors, and 23 melanoma tumors and functionally characterized the identified novel mTOR mutations in vitro and in vivo. We identified a novel point mutation A1256G in ATC cell line and G7076A in melanoma tumor in exon 9 and exon 51 of the mTOR gene, respectively. Over-expression of the corresponding mTOR mutants H419R and G2359E created through induced mutagenesis showed markedly elevated protein kinase activities associated with the activation of mTOR/p70S6K signaling in HEK293T cells. Stable expression of the two mTOR mutants in NIH3T3 cells strongly activated the mTOR/p70S6K signaling pathway and induced morphologic transformation, cell focus formation, anchorage-independent cell growth, and invasion. Inoculation of these mutant-expressing cells in athymic nude mice induced rapid tumor development, showing their driving oncogenicity. We also demonstrated that transfection with the novel mutants conferred cells high sensitivities to the mTOR inhibitor temsirolimus. We speculate that human cancers harboring these mTOR mutations, such as ATC and melanoma, may be effectively treated with inhibitors targeting mTOR.

Genetic-guided Risk Assessment and Management of Thyroid Cancer.

Controversies exist on how to optimally manage thyroid cancer because the prognosis is often uncertain based on clinical backgrounds. This can now be helped with prognostic genetic markers in thyroid cancer, exemplified by BRAF V600E and TERT promoter mutations, which have been well characterized and widely appreciated. The genetic duet of BRAF V600E/RAS and TERT promoter mutations is a most robust prognostic genetic pattern for poor prognosis of differentiated thyroid cancer. The high negative predictive values of the prognostic genetic markers are equally valuable. The best prognostic value of genetic markers in thyroid cancer is achieved through a clinical risk level-based and genotype-individualized manner.

BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.

Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer.

The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression. Elevated TERT functions as a strong oncoprotein, robustly promoting aggressive behaviors of cancer cells and tumor development. We thus identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of GABPB promoter plays a key role in functionally bridging the two oncogenes in cooperatively promoting oncogenesis, providing important cancer biological and clinical implications.