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Fig A1. Multivariate Cox proportional hazards regression analysis of mortality risk with restricted cubic splines (RCS) in patients with conventional papillary thyroid cancer (CPTC). (A) A continuous and nearly linear association between patient age and CPTC-specific mortality was observed in all patients. (B) The association was linear and even steeper in patients with BRAF V600E mutation. (C) A linear association was not seen in patients with wild-type BRAF. The blue line represents the fitted line of the association between patient age and the estimated hazard ratio (HR) of mortality risk after adjustment; the shaded region represents the 95% CI. The models were adjusted for the following clinicopathologic characteristics: patient sex, tumor size, extrathyroidal extension, lymph node metastasis, distant metastases, administered activities of radioactive iodine, and study center. The RCS plots were performed with the age of 45 years as the reference for HR calculation. (D) Specific HRs and 95% CIs were calculated for the indicated age points. (*) Significantly different HRs in reference to patient age of 45 years. Because of the small number of deaths in patients younger than age 45 years, there were large variations in log HRs in patients with CPTC harboring only wild-type BRAF in the young age ranges. Consequently, different y-axis scales are used for log HR for panels A, B, and C. 

Fig A1. Multivariate Cox proportional hazards regression analysis of mortality risk with restricted cubic splines (RCS) in patients with conventional papillary thyroid cancer (CPTC). (A) A continuous and nearly linear association between patient age and CPTC-specific mortality was observed in all patients. (B) The association was linear and even steeper in patients with BRAF V600E mutation. (C) A linear association was not seen in patients with wild-type BRAF. The blue line represents the fitted line of the association between patient age and the estimated hazard ratio (HR) of mortality risk after adjustment; the shaded region represents the 95% CI. The models were adjusted for the following clinicopathologic characteristics: patient sex, tumor size, extrathyroidal extension, lymph node metastasis, distant metastases, administered activities of radioactive iodine, and study center. The RCS plots were performed with the age of 45 years as the reference for HR calculation. (D) Specific HRs and 95% CIs were calculated for the indicated age points. (*) Significantly different HRs in reference to patient age of 45 years. Because of the small number of deaths in patients younger than age 45 years, there were large variations in log HRs in patients with CPTC harboring only wild-type BRAF in the young age ranges. Consequently, different y-axis scales are used for log HR for panels A, B, and C. 

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Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age...

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Background The aim of this study was to investigate the expression of the BRAF V600E gene mutation and the RET/PTC gene rearrangement in the progression of papillary thyroid carcinoma (PTC) in 50 patients from Inner Mongolia. Material/Methods Clinical data, blood, and tissue samples were obtained from 50 patients with PTC and ten patients with ben...

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... Thyroid cancer (TC) is the most common type of endocrine malignancy, and its incidence has rapidly increased in recent decades 1 . According to the cancer statistics, the incidence rate of thyroid cancer is ranked ninth with the global incidence ratio of women is 10.2 per 100,000 people, which is three times that of men, and the incidence of thyroid cancer has continued to increase in many countries since the 1980s [2][3][4] . ...
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Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non-tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down-regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/β-catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion, in vitro and in vivo data demonstrate that PCNP as a tumor suppressor gene may serve as a novel prognostic and potential therapeutic marker in human thyroid cancer.
... In fact, the male sex really appears as an independent prognosis factor limited to patients harboring a BRAF mutation, which is by itself a prognostic factor [161]. The same is true for the age as a prognostic factor [162] although discussed as putatively less important than pTERT (telomerase reverse transcriptase) genetic alterations, which would deserve to be explored also, regarding the male gender were associated with poorer prognosis. It should be stressed that the frequency of BRAF mutation does not differ between men and women, in contrast to what is observed between younger and older patients and to the apparent higher frequency, 38.4%, of TERT promoter mutations in men (versus 22.8% in women) in a meta-analysis including eight studies [163]. ...
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Differentiated thyroid cancers are more frequent in women than in men. These different frequencies may depend on differences in patient’s behavior and in thyroid investigations. However, an impact on sexual hormones is likely, although this has been insufficiently elucidated. Estrogens may increase the production of mutagenic molecules in the thyroid cell and favor the proliferation and invasion of tumoral cells by regulating both the thyrocyte enzymatic machinery and the inflammatory process associated with tumor growth. On the other hand, the worse prognosis of thyroid cancer associated with the male gender is poorly explained.
... THCA is a common endocrine malignant neoplasm, but its prognosis is satisfying [3]. Therefore, the incidence of THCA has increased rapidly, but the lethality ratio remains flat [4]. For low-risk THCA, this reduction in the degree of treatment involves the degree of surgery, including total thyroidectomy, lobectomy, or surgery without active monitoring, and also, indications of radioactive iodine (RAI) involved are used [5]. ...
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Thyroid cancer (THCA) is a common endocrine malignant tumor, and its global incidence of THCA has increased significantly. Neurexin 2 (NRXN2) is involved in the progression of some diseases. Nevertheless, it is still elusive towards the clinical implication and function of NRXN2 in THCA. As The Cancer Genome Atlas (TCGA) data demonstrated, we conducted a study to explore the links between NRXN2 expression and clinical features. Additionally, our data exhibited that, compared to normal thyroid tissues, NRXN2 showed low expression in THCA tissues. 20 important genes associated with NRXN2 were screened and identified. KEGG analysis data displayed that NRXN2 exhibited a link to the neuronal system, insulin secretion modulation, energy metabolism integration, muscle contraction, cardiac conduction, and neural adhesion molecule 1 (NCAM1) interactions. Our results in depth affirmed that NRXN2 was decreased in the tissues and cell lines of THCA patients. Functionally, we proved that overexpressing NRXN2 resulted in an inhibition of THCA cell proliferation, migration, and invasion in vitro. Collectively, our study demonstrated that, for the first time, NRXN2 behaved as an inhibitor of neoplasm and a promising biomarker in THCA.
... In recent years, the incidence rate of thyroid cancer has been increasing and becoming the most common endocrine malignancy (1,2). Papillary thyroid cancer (PTC) is the most common subtype, accounting for about 80% of all thyroid cancers (3). Although the degree of malignancy of PTC is low and the prognosis is usually good, many PTC patients will have tumor recurrence after operation (4,5). ...
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Background: Papillary thyroid cancer (PTC) is a common endocrine malignancy, and its incidence rate has been increasing in recent years. Long noncoding RNAs (lncRNAs) participate in cell biological processes through a variety of regulatory ways, and play an essential role in tumor development. Methods: This study explored the expression of lncRNA small nucleolar RNA host gene 6 (SNHG6) in PTC by bioinformatics analysis, and quantitative real-time PCR (qRT-PCR). Cell counting kit-8 (CCK-8) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to study the effect of SNHG6 on the proliferation of PTC cells. Luciferase reporter gene assay and western blot were used to study the mechanism. Results: SNHG6 was highly expressed in PTC tissue samples and cell lines. In vitro, overexpression of SNHG6 promoted the proliferation of PTC cells, while silencing SNHG6 inhibited the proliferation of PTC cells. miR-186 is the downstream target of SNHG6. SNHG6 regulates the proliferation of PTC cells through miR-186. In addition, CDK6 is the target gene of miR-186, which can inhibit the expression of CDK6 protein. SNHG6 can promote the expression of CDK6 by regulating miR-186. Conclusions: SNHG6 is highly expressed in PTC and can promote the proliferation of PTC cells by regulating the miR-186/CDK6 axis, which is expected to become a potential therapeutic target for PTC.
... The most common metastatic site of TC is lung (7), followed by bone, and occasionally brain and liver (8,9). DTC is a unique malignancy in which age at diagnosis can be an independent risk factor for prognosis (10,11). In 2016, the American Joint Committee on Cancer (AJCC) released eighth edition of the AJCC/TNM cancer staging manual, and changed the age cutoff from 45 years to 55 years for the DTC prognostic staging system (12). ...
... Besides age, BRAF V600E mutation was also an important risk factor for poor prognosis in TC patients (27,28). Previous studies indicated that age was a continuous mortality risk factor in patients with BRAF V600E mutation, especially for patients who were ≥ 75 years or male patients ≥ 60 years (11,29). Our conclusions were partly in line with them. ...
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Background: To investigate the relationship between age and cancer-specific mortality in thyroid cancer (TC) with lung-metastasis. Methods: 1,418 patients with initial distant metastases from Surveillance, Epidemiology and End Results databases were investigated. Patients with median follow-up time of 8 months [interquartile range (IQR), 2–27] and median age of 66 years (IQR, 55-76) were divided into five groups by age and the association between age and TC-specific mortality was analyzed. Results: The TC-specific mortality rates were 32.78% (118/360), 46.71% (156/334), 53.93% (199/369), 58.96% (158/268) and 82.76% (72/87) for patients with age of ≤55 years,56-65 years, 66-75 years, 76-85 years and >85 years. Kaplan-Meier curves showed that TC-specific mortality rate was associated with increased age (p < 0.001). Compared with patients ≤55 years, patients of 56-65 years, 66-75 years, 76-85 years and >85 years had significantly higher hazard ratios (HRs) of 1.69(1.26-2.26), 1.97 (1.47-2.64), 2.18(1.59-2.99) and 3.24(2.08-5.06) after adjustments for gender, tumor size and radiation therapy (all p < 0.001). In TC with initial lung-metastasis, compared with patients ≤55 years, patients of 56-65 years, 66-75 years, 76-85 years and >85 years had significantly higher adjusted HRs of 1.68(1.20-2.36, p=0.003), 2.18(1.57-3.02), 2.16(1.51-3.08) and 2.91(1.79-4.75) (p < 0.001). Similar results could be obtained in papillary thyroid cancer. Conclusions: The TC-specific mortality increased with age in TC patients with initial lung-metastasis, which suggested that further risk stratification based on age was necessary for TC over 55 years with lung-metastasis. Individual treatment strategy maybe recommended for patients over 85 years.
... This study included a total of 2638 patients with PTC (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 (IQR 35-58) years at diagnosis and median follow-up time of 58 (IQR 26-107) months as previously documented ( Table 1). 26 All patients received total or near-total thyroidectomy. Therapeutic neck lymph node dissection and, sometimes, prophylactic central neck dissection (pCND) were performed as clinically indicated. ...
... Diagnoses of PTC were pathologically established using the World Health Organization criteria as previously described. 23,24,26 Radioiodine-131 treatments, thyroid-stimulating hormone (TSH) suppression, and other postsurgical managements were pursued following standard clinical practice. Recurrence of PTC referred to recurrent/persistent disease based on standard biochemical (thyroglobulin) and structural (cytologic, histologic, and radiographic) criteria. ...
... Where Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab286/6323355 by Endocrine Society Member Access 3 user on 23 July 2021 A c c e p t e d M a n u s c r i p t 7 required, informed patient consent for the use of PTC specimens and clinicopathological information was obtained as described previously. 23,24,26 BRAF V600E mutation was examined by Sanger's sequencing of exon 15 of the BRAF gene on genomic DNA isolated from primary PTC tumors. 23,24,26 BRAF mutation status was retrospectively examined for the research and did not affect the clinical treatment selection. ...
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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, 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 (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 BRAFV600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAFV600E patients; mortality rates were 2/659 (0.3%) versus 4/321 (1.2%) in non-LNM versus 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 BRAFV600E CPTC, morality rates were 7/515 (1.4%) versus 28/363 (7.7%) in non-LNM versus LNM patients (P<0.001), corresponding to 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 BRAFV600E versus 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.
... Only 4.8% had a heterogeneous status for this mutation, which was observed in patients with a disease's recurrent course. In turn, there is information about the protective effect of the BRAF-V600E mutation and a decrease in the likelihood of lung damage in papillary thyroid cancer (Shen et al., 2018). Despite the previous data of unfavorable prognosis in mutant b-RAF protein turnover, it is obtained to be a sign of response to radioiodine therapy in PTC (Califano et al., 2018). ...
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Objective: The aim of this study was investigation the AKT / mTOR signaling pathway components, transcriptional and growth factors, as well as steroid hormone receptors and nuclear factors Brn-3α and TRIM16 expression in the tissue of the primary thyroid tumor and metastases, depending on the BRAF- V600E status. Material and methods: The study was enrolled 20 patients with PTCs, who underwent surgical treatment. They were divided into negative BRAF-V600E status (12 people), positive BRAF-V600E status (8 patients). Mutation status was assessed in paired metastatic tissue samples. The molecular marker expression was determined by real-time PCR. The Real-time-PCR-BRAF-V600E reagent kit evaluated the BRAF-V600E mutation. Results: A decrease in the PDK kinase, PTEN, VHL mRNA level in primary cancers was noted, compared with metastases' tissue. An increase in AKT, GSK-3β, mTOR, 70s 6 kinase was revealed in cancers with point mutation compared with the primary tumor without a mutation. Positive mutation status was accompanied by an increase in NF-κB p65, NF-κBp50, VEGF HIF-2 VHL level compared to the primary tumor with negative BRAF-V600E status. In the metastases with the BRAF-V600E point mutation, a decrease in the PDK kinase, HIF-1; VHL; TRIM16, and ERα expression was observed, compared to lymph node metastases (LNMs) without the mutation. The concordance in the BRAF-V600E tumor status and LNMs was observed only in 50% of patients. If the BRAF gene status did not match PTCs and LNMs, an increase in the mTOR, NFkBp65, VHL, and ERα mRNA levels was found in the PTCs. In LNMs, there was an increase in the c-RAF PTEN NFkBp65 VHL expression compared to non-concordant ones. Conclusion: The heterogeneity in the primary tissue's expression profile and metastases was noted. The BRAF-V600E mutation can affect the molecular characteristics both in the primary cancers and metastases. The discrepancy between the mutant status and the molecular factors expression variability in the primary tumor and LNMs determines its progression.
... A higher risk of death has also been described with BRAF-mutated thyroid cancers, on the order of 2.66-fold higher [99] . It has been reported that male gender is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients [100] . Moreover, these same authors identified age-associated mortality risk in PTC as dependent on BRAF status [101] . ...
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Incidental lesions of the thyroid are increasingly discovered as the prevalence of medical imaging escalates. The likelihood of malignancy must be assessed for each of these incidentalomas. The utility of the metabolic data derived from the identification of these lesions on PET/CT imaging is unclear. The overall rate of detection of thyroid incidentalomas on PET/CT is estimated at 1.5%-4.2%. However, this rate varies by the pattern of uptake. Several studies have evaluated predictive measures such as maximal standardized uptake value (SUVmax) and radiomics. However, no definitive conclusion has been reached. Given that the majority of PET/CT scans are performed in the context of malignancy, we recommend first assessing the general condition and life expectancy of patients when PET-detected thyroid incidentalomas are unveiled. We also recommend considering observation versus diagnostic workup with further imaging and/or fine-needle aspiration and cytology.
... An association between BRAF mutation positivity and aggressive tumor phenotype (extrathyroidal extension, lymph node metastasis) hes been reported, with a higher risk of recurrent and persistent disease [5,6], especially when TERT promoter mutation coexists [7,8]. Moreover, a linear association between TC mortality and the age of patients with BRAF V600E mutations has been observed (independent of other clinicopathologic risk factors) [9]. Retrospective multicenter studies have demonstrated that the presence of BRAF V600E mutation is significantly associated with poorer PTC outcome [6] and increased cancer-related mortality among patients with PTC [10]. ...
... Other data associates BRAF V600E with reduced follicular cell differentiation and lower iodine uptake and metabolism [11]. Some authors claim age and male sex to be strong, continuous, and independent mortality risk factors in patients with BRAF V600E mutation, but not in patients with wild-type BRAF [9,12],;-others do not report a negative prognostic impact of BRAF V600E mutation status on survival [13], or for aggressive tumor behavior in conventional and follicular variants of PTC [14,15]. The same discussion persists as to how the genetic profile of TC is translated to its US aspect.US features of high risk of malignancy, according to EU-TIRADS classification, such as blurred margins and microcalcifications were demonstrated to be independent predictors of BRAF V600E presence [12]. ...
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The data demonstrating a correlation between sonographic markers of malignancy of thyroid cancer (TC) and its genetic status are scarce. This study aimed to assess whether the addition of genetic analysis at the preoperative step of TC patients’ stratification could aid their clinical management. The material consisted of formalin-fixed paraffin-embedded tumor fragments of 49 patients who underwent thyroidectomy during the early stages of papillary TC (PTC). Tumor DNA and RNA were subjected to next-generation sequencing (NGS) on Ion Proton using the Oncomine™ Comprehensive Assay panel. We observed a significant correlation between BRAF V600E and a higher EU-TIRADS score (p-value = 0.02) with a correlation between hypoechogenicity and taller-than-wide tumor shape in analysed patients. There were no other significant associations between the identified genetic variants and other clinicopathological features. For TC patient’s stratification, a strong suspicion of BRAF V600E negativity in preoperative management of TC patients could limit the over-treatment of asymptomatic, very low-risk, indolent disease and leave room for active surveillance.
... A BRAF V600E point mutation on exon 15 is frequently detected in PTC, accounting for more than 90% of all BRAF mut in TC. BRAF mut is present in about 45% PTCs [25] and has been associated, in some studies, with features of clinical aggressiveness such as older age, larger tumors, extrathyroidal extension (ETE), lymph node metastases (LNM), higher stage, and poorer prognosis [26,27]. The impact of BRAF mut in PTC DM, lack of response to radioiodine (RAI) therapy, and mortality are still controversial [10,26,[28][29][30]. ...
... Genetic characterization of the series of tumors regarding BRAF, RAS (NRAS, HRAS, and KRAS), and TERTp mutations was performed as previously reported [9,19,27]. Primer design was performed accounting for the most frequent regions mutated in PTC, namely, BRAF codon 600, NRAS codon 61, HRAS and KRAS codons 12, 13, and 61, and TERTp-124, and −146 regions. ...
... This lack of association was corroborated by other studies [44][45][46]. Some studies have shown that older age and male gender are strong and independent risk factors for PTC-specific mortality in patients with BRAF mut tumors, but not in patients with BRAF wt tumors [27,47]. We did not find similar results in our series. ...
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Full-text available
Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002-2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients' outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.