Journal articles on the topic 'PTC mutation'
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Liu, Xiaoli, Justin Bishop, Yuan Shan, Sara Pai, Dingxie Liu, Avaniyapuram Kannan Murugan, Hui Sun, Adel K. El-Naggar, and Mingzhao Xing. "Highly prevalent TERT promoter mutations in aggressive thyroid cancers." Endocrine-Related Cancer 20, no. 4 (June 13, 2013): 603–10. http://dx.doi.org/10.1530/erc-13-0210.
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Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
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Rusinek, Dagmara, Aleksandra Pfeifer, Jolanta Krajewska, Malgorzata Oczko-Wojciechowska, Daria Handkiewicz-Junak, Agnieszka Pawlaczek, Jadwiga Zebracka-Gala, et al. "Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients." International Journal of Molecular Sciences 19, no. 9 (September 6, 2018): 2647. http://dx.doi.org/10.3390/ijms19092647.
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TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.
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Clarke, Luka A., Vanessa C. C. Luz, Szymon Targowski, Sofia S. Ramalho, Carlos M. Farinha, and Margarida D. Amaral. "Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis." Genes 12, no. 11 (November 18, 2021): 1810. http://dx.doi.org/10.3390/genes12111810.
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Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3′ and 5′ regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.
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Henke, Lauren E., John D. Pfeifer, Thomas J. Baranski, Todd DeWees, and Perry W. Grigsby. "Long-term outcomes of follicular variant vs classic papillary thyroid carcinoma." Endocrine Connections 7, no. 12 (December 2018): 1226–35. http://dx.doi.org/10.1530/ec-18-0264.
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The majority of papillary thyroid carcinoma (PTC) cases comprise classic papillary (C-PTC) and follicular variant (FV-PTC) histologic sub-types. Historically, clinical equivalency was assumed, but recent data suggest C-PTC may have poorer outcomes. However, large single-institution series with long-term outcomes of C-PTC and FV-PTC, using modern pathologic criteria for FV-PTC, are needed. Our objective was to compare prevalence and impact of clinicopathologic factors, including BRAF mutation status, on long-term outcomes of C-PTC and FV-PTC. We hypothesized that patients with C-PTC would have higher risk disease features and worse survival outcomes. This retrospective study included 1293 patients treated at a single, US academic institution between 1943 and 2009 with mean follow-up of 8.6 years. All patients underwent either partial or total thyroidectomy and had invasive C-PTC or FV-PTC per modern pathology criteria. Primary study measurements included differences in recurrence-free survival (RFS), disease-specific survival (DSS) and associations with clinicopathologic factors including the BRAF mutation. Compared to FV-PTC, C-PTC was associated with multiple features of high-risk disease (P < 0.05) and significantly reduced RFS and DSS. Survival differences were consistent across univariate, multivariate and Kaplan–Meier analyses. BRAF mutations were more common in C-PTC (P = 0.002). However, on Kaplan–Meier analysis, mutational status did not significantly impact RFS or DSS for patients with either histologic sub-type. C-PTC therefore indicates higher-risk disease and predicts for significantly poorer long-term outcomes when compared to FV-PTC. The nature of this difference in outcome is not explained by traditional histopathologic findings or by the BRAF mutation.
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Choi, Yun-Suk, Seong-Woon Choi, and Jin-Wook Yi. "Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution." Journal of Clinical Medicine 10, no. 10 (May 18, 2021): 2179. http://dx.doi.org/10.3390/jcm10102179.
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Background: Papillary thyroid cancer (PTC) has the highest cancer incidence in Korea. It is known that some thyroid cancers have aggressive clinical behavior and a poor prognosis. Genomic studies have described some somatic mutations that are related to the aggressive features of thyroid cancer, such as the BRAFV600E mutation. Recently, TERT promoter mutations were identified and reported as poor prognostic factors in PTC. Our aim was to identify the frequency and clinical impact of TERT promoter mutation in PTC. Methods: Analysis of both BRAFV600E and TERT promoter mutations in thyroidectomy specimens began in February 2019. As of December 2020, 622 patients had been tested. Data were prospectively collected and retrospectively reviewed to ascertain clinical and pathologic variables. Results: TERT promoter mutations were identified in 13 patients (2.09%); 12 had the C228T mutation, and one had the C216T mutation. In total, ten patients had the BRAFV600E mutation. TERT promoter mutation was significantly associated with advanced age (46.795 ± 12.616 versus 65.692 ± 13.628 years, p < 0.001), large tumor size (1.006 ± 0.829 versus 2.285 ± 1.938 cm, p = 0.035), extrathyroidal extension, surgical margin involvement, angioinvasion, BRAFV600E mutation and advanced TNM stage, a higher MACIS score and a high proportion of radioactive iodine therapy application. Logistic regression showed that lymphatic and angioinvasion and BRAFV600E mutation were predictive of TERT promoter mutation. Conclusions: Our study is the first to report the prospective results of TERT promoter mutations at a single tertiary hospital in Incheon, Korea. PTC with TERT promoter mutation was associated with more aggressive behavior than PTC with wild-type TERT gene status.
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Liu, Jie, Huizheng Li, Rong Du, Nan Fang, Jingbo Zhang, Yu Tang, Jianwei Wang, and Qixi Wu. "Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17574-e17574. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17574.
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e17574 Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.
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Chakraborty, Dhritiman, Sunil Shakya, Sanjana Ballal, Shipra Agarwal, and Chandrasekhar Bal. "BRAFV600E and TERT promoter mutations in paediatric and young adult papillary thyroid cancer and clinicopathological correlation." Journal of Pediatric Endocrinology and Metabolism 33, no. 11 (November 26, 2020): 1465–74. http://dx.doi.org/10.1515/jpem-2020-0174.
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AbstractObjectivesThe primary objective of this study was to determine the prevalence of BRAFV600E and TERTpromoter mutations in paediatric and young adult patients with papillary thyroid carcinoma (PTC) and the secondary objective, to assess their association with clinicopathological features.MethodsPatients ≤20 years who underwent surgery for differentiated thyroid cancer (DTC) from 2005 to 2018 were consecutively enrolled for BRAFV600E and TERTpromoter mutations analysis and records analysed for the association of aggressive features. Univariate analysis and multivariate logistic regression were used to identify the independent predictors of BRAFV600E mutations.ResultsAmong 100 patients with DTC, 68 patients were ≤18 years and the remaining 30 patients were >18 years of age with a median age of 17 years (IQR 14–19 years) 98 patients had PTC and 2 had FTC. BRAFV600E mutation was present in 14/98 (14.3%) PTC and TERTpromoter mutation noted in none. Multivariate analysis identified RAI refractoriness (OR:10.57, 95% CI: 2.6 to 41.6, P-0.0008) as an independent factor associated with BRAFV600E mutation. 17 patients with distant metastases were negative for both BRAFV600E or TERTpromoter mutation. No significant association was observed between age, gender, PTC variants, extra-thyroidal extension, lymphovascular invasion, multifocality, RAI administration and event rate with BRAFV600E mutation. Irrespective of BRAFV600E mutation, radioiodine refractory status (p-0.0001) had a reduced EFS probability.ConclusionIn paediatric & young adult PTC, TERTpromoter mutation is absent and BRAFV600E mutation is not associated with distant metastasis. The prevalence rate of the BRAFV600E mutation is much lower compared to adult PTC patients.
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Barzon, Luisa, Giulia Masi, Isabella Merante Boschin, Enrico Lavezzo, Monia Pacenti, Eric Casal Ide, Antonio Toniato, Stefano Toppo, Giorgio Palù, and Maria Rosa Pelizzo. "Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma." European Journal of Endocrinology 159, no. 1 (July 2008): 77–80. http://dx.doi.org/10.1530/eje-08-0239.
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IntroductionActivating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.CaseScreening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600–S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.ConclusionsThis study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.
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Siraj, Sarah, Tariq Masoodi, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Rong Bu, et al. "APOBEC SBS13 Mutational Signature—A Novel Predictor of Radioactive Iodine Refractory Papillary Thyroid Carcinoma." Cancers 14, no. 6 (March 21, 2022): 1584. http://dx.doi.org/10.3390/cancers14061584.
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Standard surgery followed by radioactive iodine (131I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43–647.22) and TERTp mutation (OR 41.3, 95% CI 4.35–391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC.
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Durand, Stéphanie, Carole Ferraro-Peyret, Mireille Joufre, Annie Chave, Françoise Borson-Chazot, Samia Selmi-Ruby, and Bernard Rousset. "Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features." Endocrine-Related Cancer 16, no. 2 (June 2009): 467–81. http://dx.doi.org/10.1677/erc-08-0081.
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About 60–70% of papillary thyroid carcinomas (PTC) present a BRAFT1799A gene mutation or a rearrangement of RET gene (RET/PTC). In this study, we examined whether PTC without BRAFT1799A mutation and without RET/PTC rearrangement named PTC-ga(−) were distinguishable from PTC-ga(+) (with one or the other gene alteration) on the basis of gene expression characteristics. We analyzed the mutational state of 116 PTC and we compared gene expression profiles of PTC-ga(+) and PTC-ga(−) from data of a 200 gene macroarray and quantitative PCR. Seventy five PTC were PTC-ga(+) and 41 were PTC-ga(−). Unsupervised analyses of macroarray data by hierarchical clustering led to a complete segregation of PTC-ga(+) and PTC-ga(−). In a series of 42 genes previously recognized as PTC ‘marker’ genes, 22 were found to be expressed at a comparable level in PTC-ga(−) and normal tissue. Thyroid-specific genes, TPO, TG, DIO1, and DIO2 were under-expressed in PTC-ga(+) but expressed at a normal level in PTC-ga(−). A few genes including DUOX1 and DUOX2 were selectively dys-regulated in PTC-ga(−). Tumor grade of PTC-ga(−) was lower than that of PTC-ga(+). There was a strong association between the mutational state and histiotype of PTC; 81% of PTC follicular variants were corresponded to PTC-ga(−), whereas 84% of PTC of classical form were PTC-ga(+). In conclusion, we show that PTC without BRAFT1799A mutation or RET/PTC rearrangement, mainly corresponding to follicular variants, maintain a thyroid differentiation expression level close to that of normal tissue and should be of better prognosis than PTC with one or the other gene alteration.
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Pamedytyte, Daina, Vaida Simanaviciene, Dalia Dauksiene, Enrika Leipute, Aurelija Zvirbliene, Valdas Sarauskas, Albertas Dauksa, Rasa Verkauskiene, and Birute Zilaitiene. "Association of microRNA Expression and BRAFV600E Mutation with Recurrence of Thyroid Cancer." Biomolecules 10, no. 4 (April 17, 2020): 625. http://dx.doi.org/10.3390/biom10040625.
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Many miRNAs and cancer-related mutations have been proposed as promising molecular markers of papillary thyroid carcinoma (PTC). However, there are limited data on the correlation between miRNA expression, BRAFV600E mutation, and PTC recurrence. Therefore, to evaluate the potential of BRAFV600E mutation and five selected miRNAs (-146b, -222, -21, -221, -181b) in predicting PTC recurrence, these molecular markers were analyzed in 400 formalin-fixed, paraffin-embedded PTC tissue specimens. The expression levels of miRNAs were measured using qRT-PCR. It was demonstrated that expression levels of all analyzed miRNAs are significantly higher in recurrent PTC than in non-recurrent PTC (p < 0.05). Moreover, higher expression levels of miR-146b, miR-222, miR-21, and miR-221 were associated with other clinicopathologic features of PTC, such as tumor size and lymph node metastases at initial surgery (p < 0.05). No significant differences in the frequency of BRAFV600E mutation in recurrent PTC and non-recurrent PTC were determined. Our results suggest that miRNA expression profile differs in PTC that is prone to recurrence when compared to PTC that does not reoccur after the initial surgery while BRAFV600E mutation frequency does not reflect the PTC recurrence status. However, the prognostic value of the analyzed miRNAs is rather limited in individual cases as the pattern of miRNA expression is highly overlapping between recurrent and non-recurrent PTC.
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Gąsior-Perczak, Danuta, Artur Kowalik, Agnieszka Walczyk, Monika Siołek, Krzysztof Gruszczyński, Iwona Pałyga, Estera Mikina, et al. "Coexisting Germline CHEK2 and Somatic BRAFV600E Mutations in Papillary Thyroid Cancer and Their Association with Clinicopathological Features and Disease Course." Cancers 11, no. 11 (November 7, 2019): 1744. http://dx.doi.org/10.3390/cancers11111744.
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BRAFV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the risk of PTC. Coexistence of both mutations is expected to be associated with poorer clinical course. We evaluated the prevalence of concomitant CHEK2 and BRAFV600E mutations and their associations with clinicopathological features, treatment response, and disease course in PTC patients. The study included 427 unselected PTC patients (377 women and 50 men) from one center. Relationships among clinicopathological features, mutation status, treatment response, and disease outcomes were assessed. Mean follow-up was 10 years. CHEK2 mutations were detected in 15.2% and BRAFV600E mutations in 64.2% patients. Neither mutation was present in 31.4% cases and both BRAFV600E and CHEK2 mutations coexisted in 10.8% patients. No significant differences in clinicopathological features, initial risk, treatment response, or disease outcome were detected among these patient groups. CHEK2 mutations were significantly associated with older age, while BRAFV600E was significantly associated with older age and extrathyroidal extension. The coexistence of both mutations was not associated with more aggressive clinicopathological features of PTC, poorer treatment response, or disease outcome.
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Joshi, Tripti, Ruta Gupta, Luisa Fernanda Olaya A, Bing Yu, Susan McLennan, and Elizabeth Lian Chua. "Molecular Genetics in a Cohort of Patients With Concurrent PTC and Melanoma." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1027. http://dx.doi.org/10.1210/jendso/bvab048.2102.
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Abstract PTC and melanoma are known to harbour common mutations, but this has not been extensively investigated. Targeted therapies for BRAF and PD-L1 have been used for melanoma and there are ongoing clinical trials for use of PD-L1 inhibitors in PTC but its utility is uncertain. Additionally, many of these patients have multiple cancers, so, whether they have a tumour predisposition syndrome is also unclear. Both germline and somatic mutations in BRCA1-associated protein 1 (BAP1) are associated with a wide spectrum of tumours. We hypothesized that a common genetic link may be present in our cohort of patients who have both PTC and melanoma. The aim of this study was to elucidate molecular genetics, specifically BRAF, NRAS, KRAS, KIT using OncoFocus Mass Array System as well as expression of PD-L1 and BAP1, using a standard antibody (SP263) and C-4 respectively, in an Australian cohort with concurrent PTC and melanoma. In our cohort of 21 patients (43% females, all Caucasian), melanoma was diagnosed about 8 years prior to PTC (50.3 ± 18.3 vs. 58.6 ± 12.8 years). The most common mutation was BRAFV600E seen in 88% of PTC, followed by NRAS mutation in 12% of PTC. Majority of the PTC (68%) stained negative for PD-L1. There was no significant association between PD-L1 tumour status and clinicopathologic outcomes. Interestingly, majority of multifocal, bilateral and both bilateral and multifocal PTC were PD-L1 negative (85%,69% and 69% respectively, P<0.05); only extrathyroidal extension was found to be associated with positive (≥1%) PD-L1 staining (83.3 vs.30.8; p=0.057). Regarding melanoma, clinicopathologic and mutation data were obtained for 15/21 patients and 8/15 patients respectively. Superficial spreading type of melanoma was present in 50% patients. The BRAFV600E and NRAS mutation were present in 3/8 patients each, and 2/8 patients had no mutations. PD-L1 staining was negative in 7/12 (58%) of melanoma tissues. Of the 5 cases that stained positive for PD-L1, 4 were at >25%, a much higher degree of staining compared to PTC group. Among 7 patients where data were available for both tissues, concordant mutations were found in only 2 patients (both BRAFV600E). In addition, 11 of the 21 patients had at least one other cancer apart from PTC and melanoma. Nine of the 11 patients who had more than one cancer were BRAF positive. BAP1 staining was retained in the majority of PTCs and melanoma tissues, indicating no loss of BAP1 protein. PTC and melanoma both share molecular markers including BRAF, NRAS, PD-L1 as shown in our cohort. This is the largest study describing the mutation status of both PTC and melanoma. It is also the only study describing the PD-L1 and BAP1 expression in PTC and melanoma. BRAFV600E was the most common mutation. Majority of the PTC and melanoma stained negative for PD-L1. BAP1 expression was retained in both either PTC and melanoma tissues thus making presence of BAP1 tumour predisposition syndrome unlikely.
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Jin, Meihua, Dong Eun Song, Jonghwa Ahn, Eyun Song, Yu-Mi Lee, Tae-Yon Sung, Tae Yong Kim, et al. "Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas." Cancers 13, no. 4 (February 20, 2021): 892. http://dx.doi.org/10.3390/cancers13040892.
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Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.
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Vidinov, K., R. Dodova, P. Mitev, A. Mitkova, I. Dimitrova, A. Shinkov, R. Ivanova, V. Mitev, and R. Kaneva. "Clinicopathological Significance of BRAF (V600E), NRAS (Q61K) and TERT (C228T, C250T and SNP Rs2853669) Mutations in Bulgarian Papillary Thyroid Carcinoma Patients." Acta Medica Bulgarica 48, no. 1 (April 1, 2021): 1–8. http://dx.doi.org/10.2478/amb-2021-0001.
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Abstract Introduction: Thyroid carcinoma is the most common endocrine cancer. Some somatic mutations in genes (BRAF, NRAS and TERT) involved in key signaling pathways and genome stability have been recently identified to play an important role in its development. Very little research has been done on their frequency and clinical relevance in Bulgarian patients with papillary thyroid cancer (PTC). This study is focused on investigating somatic mutation frequency in Bulgarian patients with PTC and their association with clinicopathologic features. Material and Methods: The study included 50 PTC from Bulgarian patients analyzed for mutations in BRAF (V600E), NRAS (Q61K), single nucleotide polymorphism (SNP) rs2853669 and TERT (C228T and C250T) genes by Sanger sequencing. The results were interpreted using Benchling and SeqScape software, and statistical analysis performed with SPSS. Results: In the studied PTC group BRAF(V600E) and TERT (C228T) mutations were found with frequency of 24% and 2%, respectively. Co-occurrence of both mutations was found in 1 patient (2%). The mutations Q61K (NRAS), and C250T (TERT) were not detected. The SNP rs2853669 was found in 18 patients (52.9%). Correlation analysis with the clinical characteristics of the patients revealed statistically significant association with larger size of the tumor for BRAF(V600E) and smaller tumor size for rs2853669. Conclusion: In the present pilot study, we found that BRAF(V600E) and rs2853669 in TERT are common among PCT patients. While the presence of BRAF V600E mutation was associated with large tumors, the presence of rs2853669 in TERT was found in the majority of PCT below 2 cm. More extensive molecular genetic analysis of TERT, BRAF or RAS mutations in larger sample is needed to further elucidate the clinically important diagnostic and prognostic biomarkers for thyroid cancer.
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Karunamurthy, Arivarasan, Federica Panebianco, Susan J. Hsiao, Jennie Vorhauer, Marina N. Nikiforova, Simion Chiosea, and Yuri E. Nikiforov. "Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules." Endocrine-Related Cancer 23, no. 4 (April 2016): 295–301. http://dx.doi.org/10.1530/erc-16-0043.
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AbstractTheEIF1AXgene mutations have been recently found in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). The prevalence of these mutations in other types of thyroid cancers and benign nodules is unknown. In this study, we analyzed the occurrence ofEIF1AXmutations in exons 2, 5, and 6 of the gene in a series of 266 thyroid tumors and hyperplastic nodules by either Sanger or next-generation sequencing (ThyroSeq v.2). In addition, 647 thyroid fine-needle aspiration (FNA) samples with indeterminate cytology were analyzed. Using surgically removed samples,EIF1AXmutations were detected in 3/86 (2.3%) PTC, 1/4 (25%) ATC, 0/53 follicular carcinomas, 0/12 medullary carcinomas, 2/27 (7.4%) follicular adenomas, and 1/80 (1.3%) hyperplastic nodules. Among five mutation-positive FNA samples with surgical follow-up, one nodule was PTC and others were benign follicular adenomas or hyperplastic nodules. Overall, among 33 mutations identified, A113_splice mutation at the intron 5/exon 6 splice site ofEIF1AXwas the most common. All four carcinomas harbored A113_splice mutation and three of them had one or more coexisting mutations, typicallyRAS. All PTC carryingEIF1AXmutations were encapsulated follicular variants. In summary, this study shows thatEIF1AXmutations occur not only in thyroid carcinomas, but also in benign nodules. The most common mutation hotspot is the A113_splice, followed by a cluster of mutations in exon 2. When found in thyroid FNA samples,EIF1AXmutations confer ~20% risk of cancer; the risk is likely to be higher in nodules carrying a A113_splice mutation and whenEIF1AXcoexists withRASmutations.
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Lupi, Cristiana, Riccardo Giannini, Clara Ugolini, Agnese Proietti, Piero Berti, Michele Minuto, Gabriele Materazzi, et al. "Association of BRAF V600E Mutation with Poor Clinicopathological Outcomes in 500 Consecutive Cases of Papillary Thyroid Carcinoma." Journal of Clinical Endocrinology & Metabolism 92, no. 11 (November 1, 2007): 4085–90. http://dx.doi.org/10.1210/jc.2007-1179.
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Abstract Context: Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation. Objective: We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class. Design: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples. Results: In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600–1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600–3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P < 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P < 0.00000006), and absence of tumor capsule (P < 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation. Conclusions: Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.
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Hardee, Steven, Manju L. Prasad, Pei Hui, Catherine A. Dinauer, and Raffaella A. Morotti. "Pathologic Characteristics, Natural History, and Prognostic Implications of BRAFV600E Mutation in Pediatric Papillary Thyroid Carcinoma." Pediatric and Developmental Pathology 20, no. 3 (February 8, 2017): 206–12. http://dx.doi.org/10.1177/1093526616689628.
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The BRAFV600E mutation is the most common genetic aberration in papillary thyroid cancer (PTC), found in up to 68% of PTC in adults where it is associated with aggressive features. The incidence of this mutation in pediatric PTC is less frequent, reported as 0%–20% in the past and up to 63% in one recent series. Data suggest the mutation is not associated with an aggressive course in children; however, there are limited numbers of reported case series, so the prognostic implications remain poorly understood. The aim of this retrospective study was to examine the histologic characteristics and clinical outcomes of BRAF positive pediatric PTC at a single institution. A 12-year retrospective review of all thyroidectomies performed at a tertiary medical center identified 59 pediatric cases with a surgical pathology diagnosis of PTC. Fifty patients had BRAFV600E mutation analysis data and were selected for further study. BRAFV600E mutations were present in 48% of cases (n = 24) and absent in 52% (n = 26). The molecular characteristics of the BRAF negative cases will further be evaluated in future studies. BRAF positive cases occurred in patients who were on average older than the BRAF negative patients. Classic histology PTC was present in both BRAF positive and negative cases; however, only cases with classic PTC histology were positive for the mutation. No patients died and BRAF mutation was not associated with an increased recurrence rate. Our study supports BRAFV600E is more common in children than previously thought and does not portend a more aggressive clinical course.
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Ebina, Aya, Yuki Togashi, Satoko Baba, Yukiko Sato, Seiji Sakata, Masashi Ishikawa, Hiroki Mitani, Kengo Takeuchi, and Iwao Sugitani. "TERT Promoter Mutation and Extent of Thyroidectomy in Patients with 1–4 cm Intrathyroidal Papillary Carcinoma." Cancers 12, no. 8 (July 30, 2020): 2115. http://dx.doi.org/10.3390/cancers12082115.
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There are concerns regarding overtreatment in papillary thyroid carcinoma (PTC). BRAF V600E and TERT promoter mutations play important roles in the development of PTC. However, initial surgical approaches for PTC based on genetic characteristics remain unclear. The present study aimed to identify genetic mutations as predictors of prognosis and to establish proper indications for lobectomy (LT) in patients with 1–4 cm intrathyroidal PTC. Prospectively accumulated data from 685 consecutive patients with PTC who underwent primary thyroid surgery at the Cancer Institute Hospital, Tokyo, Japan, between 2001 and 2012 were retrospectively reviewed. Of the 685 patients examined, 538 (78.5%) had BRAF V600E mutation and 133 (19.4%) had TERT promoter mutations. Patients with TERT promoter mutations displayed significantly worse outcomes than those without mutations (10-year cause-specific survival (CSS): 73.7% vs. 98.1%, p < 0.001; 10-year disease-free survival (DFS): 53.7% vs. 93.3%, p < 0.001). As for extent of thyroidectomy among TERT mutation-negative patients with 1–4 cm intrathyroidal PTC, patients who underwent LT showed no significant differences in 10-year CSS and 10-year DFS compared to patients who had total thyroidectomy (TT) under propensity score-matching. Avoiding TT for those patients indicates a possible pathway to prevent overtreatment and reduce postoperative complications.
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Plaksa, I. L., M. R. Savchuk, N. V. Shved, N. A. Savelov, D. N. Khmelkova, А. A. Isaev, and R. V. Deev. "Mutation profile of the tall cell variant of papillary thyroid carcinoma: analysis of 5 cases using wide-panel next-generation sequencing." Head and Neck Tumors (HNT) 11, no. 1 (April 24, 2021): 78–85. http://dx.doi.org/10.17650/2222-1468-2021-11-1-78-85.
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The study objective is to analyze the mutation profile of the tall cell variant (TCV) of papillary thyroid carcinoma (PTC).Materials and methods. The main inclusion criteria according to the WHO classification (2017) was PTC composed of at least 30 % of tall cells. Genetic examination was conducted using the FoundationOne CDx assay (USA) with median depth of coverage of >500x. This study included 5 patients (1 man and 4 women) with a mean age of 52.6 years (range: 48-56 years). The tumor size varied between 0.4 x 0.5 cm and 11.0 x 9.0 cm. All patients have undergone surgical treatment: hemithyroidectomy for patient No. 1 with a small tumor (pT1b); thyroidectomy for patient No. 2 (pT3b); extensive thyroidectomy with the removal of paratracheal tissue for patients No. 3, 4, and 5 (No. 3 - pT3bN0; No. 4 - pT3bN1b; No. 5 - pT3bN1b). Three out of the five patients also had adenomatous goiter. The mean follow-up time was 3.4 to 5.2 years.Results. Tumors in all patients were characterized by low mutational load (0 to 4 mutations per 1 million nucleotides (megabase)) and no microsatellite instability. All study participants were found to have p.V600E mutation in the BRAF gene; two patients had c.-124C>T mutation in the promoter region of the TERT gene. All patients carried mutations with unknown clinical significance: p.V562I in the EPHB1 gene (in 2 patients); mutations in the genes AR, CREBBP, EP300, ERCC4, FLT1, IKBKE, JAK2, MAF, MLL2, MST1R, MYC, MYCL1, NTRK2, TSC2 (each mutation registered in one patient). One individual with the largest tumor and the most aggressive disease was found to have amplifications of the BTG2, MAP3K1, SMAD2, and TBX3 genes.Conclusion. In 5 patients analyzed in this study, the mutation profile of TCV PTC was characterized by low mutational load, no microsatellite instability, and presence of p.V600E mutation in the BRAF gene in all cases. Some patients also had c.-124C>T mutation in the TERT gene and p.V562I mutation in the EPHB1 gene.
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Gertz, Ryan J., Yuri Nikiforov, William Rehrauer, Lee McDaniel, and Ricardo V. Lloyd. "Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population." Archives of Pathology & Laboratory Medicine 140, no. 2 (February 1, 2016): 134–39. http://dx.doi.org/10.5858/arpa.2014-0612-oa.
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Context Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population. Objective To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors. Design Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well. Results Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P = .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3–base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%). Conclusions The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.
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Wei, Xiaojing, Xiaodong Wang, Jie Xiong, Chen Li, Yixuan Liao, Yongjun Zhu, and Jingxin Mao. "Risk and Prognostic Factors for BRAFV600E Mutations in Papillary Thyroid Carcinoma." BioMed Research International 2022 (May 18, 2022): 1–13. http://dx.doi.org/10.1155/2022/9959649.
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Background. Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFV600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAFV600E mutation potential of these lesions and new prevention strategies in PTC patients. Methods. A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFV600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021. Results. The following variables were associated with an increased risk of BRAFV600E mutation in PTC patients: age ≥ 45 years ( OR = 1.39 , 95 % CI = 1.21 – 1.60 , p < 0.00001 ), male gender ( OR = 1.13 , 95 % CI = 0.99 – 1.28 , p = 0.06 ), multifocality ( OR = 1.22 , 95 % CI = 1.07 – 1.40 , p = 0.004 ), lymph node metastasis ( OR = 1.33 , 95 % CI = 0.79 – 2.23 , p = 0.28 ), extrathyroidal extension + ( OR = 1.61 , 95 % CI = 1.06 – 2.44 , p = 0.03 ), vascular invasion + ( OR = 2.04 , 95 % CI = 1.32 – 3.15 , p = 0.001 ), and tumor node metastasis stage ( OR = 1.61 , 95 % CI = 1.38 – 1.88 , p < 0.00001 ). In addition, tumor size (>1 cm) ( OR = 0.51 , 95 % CI = 0.32 – 0.81 , p = 0.005 ) and distant metastasis ( OR = 0.69 , 95 % CI = 0.22 – 2.21 , p = 0.54 ) had no association or risk with BRAFV600E mutation in PTC patients. Conclusion. Our systematic review identified the following significant risk factors of BRAFV600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAFV600E mutation in PTC patients.
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Lin, Xiaoqi, Sydney D. Finkelstein, Bing Zhu, and Jan F. Silverman. "Molecular analysis of multifocal papillary thyroid carcinoma." Journal of Molecular Endocrinology 41, no. 4 (July 15, 2008): 195–203. http://dx.doi.org/10.1677/jme-08-0063.
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Papillary thyroid carcinoma (PTC) frequently presents as a multifocal process. To study the importance of separating independent primary (IP) from intrathyroid metastatic (ITM) PTC, we examined 19 molecular markers on 42 separate tumors from 18 multifocal PTC cases. In 12 of 18 (66.7%) cases, including 6 of 12 (50%) papillary microcarcinoma cases, the same or similar profile of loss of heterozygosities (LOH) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation was demonstrated, indicating that they were from the same primary and represented ITM. Different profiles of LOHs and BRAF mutation were detected in separate tumors of 6 of 18 cases, indicating that they represented IP. Patients with ITM, including papillary microcarcinoma, had significantly increased lymph node metastasis. The frequencies of LOHs of 17q21, 17p13, 10q23, and 22q13 were higher in tumors with lymph node metastasis, suggesting that these LOHs may be important in increased lymph node metastasis. LOH of 9p21 was found at the highest frequency in PTC (53.8%), followed by 1p36 (46.2%), 10q23 (34.6%), and 22q13 (34.6%). Papillary microcarcinoma had acquired similar genomic mutations as conventional PTC, but higher frequencies of mutations of BRAF, 1p36, 18q, and 22q13 were found in the larger PTC, suggesting that they might play a role in the aggressiveness of PTC. Different profiles of mutations were observed in conventional, follicular variants, and diffuse sclerosing variant of PTC, which might influence the different morphological appearances and clinical courses. In conclusion, molecular analysis can separate multifocal IP PTC from ITM PTC, and may be more important than tumor size in predicting lymph node metastasis, aggressiveness, and prognosis of PTC.
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Espiritu, Gerard Anthony M., Joemari T. Malana, Arlie Jean Grace V. Dumasis, and Daphne C. Ang. "High Preponderance of BRAF V600E Mutation in Papillary Thyroid Carcinoma Among Filipinos: A Clinicopathologic Study." Journal of Global Oncology, no. 5 (December 2019): 1–6. http://dx.doi.org/10.1200/jgo.18.00085.
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Purpose BRAF mutation in papillary thyroid carcinoma (PTC) is associated with an aggressive phenotype, with varying incidence. We evaluated the prevalence of BRAF mutations in PTC among Filipino patients and their correlation with clinicopathologic characteristics. Patients and Methods Clinicopathologic data were retrieved from 64 sequential patients who underwent thyroidectomy from June 2016 to December 2016. BRAF mutation testing was performed using Sanger sequencing. Results Eighteen (28%) of 64 patients were diagnosed with PTC; 12 (70.59%) of 17 harbored a BRAF V600E mutation (no amplification in one patient). Demographics of patients with PTC were as follows: 13 women and five men, with median age of 46 years (range, 25 to 74 years). Fourteen patients had conventional subtype PTC; two, follicular variant; one, oncocytic variant; and one, tall-cell features. Tumor size ranged from 0.8 to 7.0 cm (median, 2.4 cm); extrathyroidal extension was present in seven (38.9%) of 18 patients, multifocality in six (33.33%) of eight, and lymph node involvement in eight (44.4%) of 18. Significant association between presence of a BRAF mutation and presence of extrathyroidal extension or lymph node involvement was not determined due to the limited sample size. Conclusion The high preponderance of BRAF mutation (70.59%) suggests some correlation with the previously reported lower 5-year survival among Filipinos. This warrants further investigation in a larger-cohort prospective study.
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Xing, Mingzhao, Douglas Clark, Haixia Guan, Meiju Ji, Alan Dackiw, Kathryn A. Carson, Matthew Kim, et al. "BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Biopsy Specimens for Preoperative Risk Stratification in Papillary Thyroid Cancer." Journal of Clinical Oncology 27, no. 18 (June 20, 2009): 2977–82. http://dx.doi.org/10.1200/jco.2008.20.1426.
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Purpose This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC). Patients and Methods We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively. Results We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation–positive patients versus 12% of BRAF mutation–negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively. Conclusion Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC.
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d’Aquino, Anne E., Tasfia Azim, Nikolay A. Aleksashin, Adam J. Hockenberry, Antje Krüger, and Michael C. Jewett. "Mutational characterization and mapping of the 70S ribosome active site." Nucleic Acids Research 48, no. 5 (February 3, 2020): 2777–89. http://dx.doi.org/10.1093/nar/gkaa001.
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Abstract The synthetic capability of the Escherichia coli ribosome has attracted efforts to repurpose it for novel functions, such as the synthesis of polymers containing non-natural building blocks. However, efforts to repurpose ribosomes are limited by the lack of complete peptidyl transferase center (PTC) active site mutational analyses to inform design. To address this limitation, we leverage an in vitro ribosome synthesis platform to build and test every possible single nucleotide mutation within the PTC-ring, A-loop and P-loop, 180 total point mutations. These mutant ribosomes were characterized by assessing bulk protein synthesis kinetics, readthrough, assembly, and structure mapping. Despite the highly-conserved nature of the PTC, we found that >85% of the PTC nucleotides possess mutational flexibility. Our work represents a comprehensive single-point mutant characterization and mapping of the 70S ribosome's active site. We anticipate that it will facilitate structure-function relationships within the ribosome and make possible new synthetic biology applications.
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Muzza, Marina, Gabriele Pogliaghi, Luca Persani, Laura Fugazzola, and Carla Colombo. "Combined Mutational and Clonality Analyses Support the Existence of Intra-Tumor Heterogeneity in Papillary Thyroid Cancer." Journal of Clinical Medicine 10, no. 12 (June 16, 2021): 2645. http://dx.doi.org/10.3390/jcm10122645.
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Despite its potential clinical impact, intra-tumor genetic heterogeneity (ITH) has been scantly investigated in papillary thyroid cancer (PTC). We studied ITH in PTC by combining, for the first time, data derived from the evaluation of the normalized allelic frequencies (NAF) of the mutation/s, using a customized MassARRAY panel, and those obtained by the HUMARA clonality assay. Among tumors with a single mutation, 80% of cases with NAF 50 ± 5% were clonal, consistent with the presence of a single mutated clone, while 20% of cases showed a polyclonal pattern, suggesting the presence of the same mutation in two or more clones. Differently, all cases with NAF < 45% were polyclonal. Among tumors with double mutation, cases with both mutations showing NAF 50 ± 5% were monoclonal, consistent with the presence of a single clone harboring both mutations. On the other hand, all cases with double mutation at NAF < 45% were polyclonal, indicating the presence of two clones with different mutations. Finally, no significant differences in the clinico-pathological characteristics were found between monoclonal and polyclonal tumors. In conclusion, the present study adds insights into the concept of ITH in PTC, which warrants attention because the occurrence of this phenomenon is likely to affect the response to targeted drugs.
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Guan, Haixia, Meiju Ji, Rong Bao, Hongyu Yu, Yangang Wang, Peng Hou, Yong Zhang, Zhongyan Shan, Weiping Teng, and Mingzhao Xing. "Association of High Iodine Intake with the T1799A BRAF Mutation in Papillary Thyroid Cancer." Journal of Clinical Endocrinology & Metabolism 94, no. 5 (May 1, 2009): 1612–17. http://dx.doi.org/10.1210/jc.2008-2390.
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Abstract Context: Epidemiological studies have indicated that high iodine intake might be a risk factor for papillary thyroid cancer (PTC), which commonly harbors the oncogenic T1799A BRAF mutation. Objective: The objective of the study was to investigate the relationship between BRAF mutation in PTC and iodine intake in patients. Subjects and Methods: We analyzed and compared the prevalences of the T1799A BRAF mutation in classical PTC of 1032 patients from five regions in China that uniquely harbor different iodine contents in natural drinking water, ranging from normal (10–21 μg/liter) to high (104–287 μg/liter). The BRAF mutation was identified by direct DNA sequencing. Results: The prevalence of BRAF mutation was significantly higher in any of the regions with high iodine content than any of the regions with normal iodine content. Overall, BRAF mutation was found in 387 of 559 PTC with high iodine content (69%) vs. 252 of 473 PTC with normal iodine content (53%), with an odds ratio of 1.97 (95% confidence interval 1.53–2.55) for the association of BRAF mutation with high iodine content (P < 0.0001). In addition, clinicopathological correlation analysis, the largest one of its type ever, showed that BRAF mutation was significantly associated with extrathyroidal invasion, lymph node metastasis, and advanced tumor stages of PTC. Conclusions: High iodine intake seems to be a significant risk factor for the occurrence of BRAF mutation in thyroid gland and may therefore be a risk factor for the development of PTC. This large study also confirmed the association of BRAF mutation with poorer clinicopathological outcomes of PTC.
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Rusinek, Dagmara, Aleksandra Pfeifer, Marta Cieslicka, Malgorzata Kowalska, Agnieszka Pawlaczek, Jolanta Krajewska, Sylwia Szpak-Ulczok, et al. "TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma." Cancers 12, no. 6 (June 17, 2020): 1597. http://dx.doi.org/10.3390/cancers12061597.
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Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(−) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs. Deregulation of pathways involved in key cell processes was observed. Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.
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Han, Jiheun, Young Lyun Oh, and Jung-Sun Kim. "Co-Occurrence of Hotspot Point Mutation and Novel Deletion Mutation of TERT Promoter in Solid Variant Papillary Thyroid Carcinoma in a Patient with Synchronous Esophageal Cancer." Diagnostics 11, no. 1 (December 22, 2020): 4. http://dx.doi.org/10.3390/diagnostics11010004.
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(1) Introduction: Telomerase reverse transcriptase (TERT) promoter mutations are associated with unfavorable clinical outcomes in papillary thyroid carcinomas (PTCs). Two substitution mutations, C228T (c.1-124C>T) and C250T (c.1-146C>T), make up most of the mutations and occur in a mutually exclusive manner. (2) Case presentation: A 72-year-old man was initially referred to a tertiary hospital for treatment of esophageal cancer. Preoperative imaging revealed a 3.2 cm thyroid nodule pathologically diagnosed as PTC on needle biopsy. The patient underwent thyroid lobectomy with esophagectomy and was finally diagnosed with synchronous solid variant PTC (SVPTC) and esophageal squamous cell carcinoma. Sanger sequencing using DNA from the thyroid tumor showed an indel mutation, c.1-132_1-124delinsT, composed of a deletion (c.1-132_1-125del) as well as a hotspot mutation (c.1-124C>T(C228T)) in the TERT promoter. (3) Conclusions: This is the first report of PTC harboring a novel deletion along with a hotspot mutation in the TERT promoter in a patient with synchronous esophageal squamous cell carcinoma.
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Vuong, Huy Gia, Uyen N. P. Duong, Ahmed M. A. Altibi, Hanh T. T. Ngo, Thong Quang Pham, Hung Minh Tran, Greta Gandolfi, and Lewis Hassell. "A meta-analysis of prognostic roles of molecular markers in papillary thyroid carcinoma." Endocrine Connections 6, no. 3 (April 2017): R8—R17. http://dx.doi.org/10.1530/ec-17-0010.
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The prognostic role of molecular markers in papillary thyroid carcinoma (PTC) is a matter of ongoing debate. The aim of our study is to investigate the impact of RAS, BRAF, TERT promoter mutations and RET/PTC rearrangements on the prognosis of PTC patients. We performed a search in four electronic databases: PubMed, Scopus, Web of Science and Virtual Health Library (VHL). Data of hazard ratio (HR) and its 95% confidence interval (CI) for disease-specific survival (DSS) and disease-free survival (DFS) were directly obtained from original papers or indirectly estimated from Kaplan–Meier curve (KMC). Pooled HRs were calculated using random-effect model weighted by inverse variance method. Publication bias was assessed by using Egger’s regression test and visual inspection of funnel plots. From 2630 studies, we finally included 35 studies with 17,732 patients for meta-analyses. TERT promoter mutation was significantly associated with unfavorable DSS (HR = 7.64; 95% CI = 4.00–14.61) and DFS (HR = 2.98; 95% CI = 2.27–3.92). BRAF mutations significantly increased the risk for recurrence (HR = 1.63; 95% CI = 1.27–2.10) but not for cancer mortality (HR = 1.41; 95% CI = 0.90–2.23). In subgroup analyses, BRAF mutation only showed its prognostic value in short-/medium-term follow-up. Data regarding RAS mutations and RET/PTC fusions were insufficient for meta-analyses. TERT promoter mutation can be used as an independent and reliable marker for risk stratification and predicting patient’s outcomes. The use of BRAF mutation to assess patient prognosis should be carefully considered.
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Xing, Mingzhao, Rengyun Liu, Xiaoli Liu, Avaniyapuram Kannan Murugan, Guangwu Zhu, Martha A. Zeiger, Sara Pai, and Justin Bishop. "BRAF V600E and TERT Promoter Mutations Cooperatively Identify the Most Aggressive Papillary Thyroid Cancer With Highest Recurrence." Journal of Clinical Oncology 32, no. 25 (September 1, 2014): 2718–26. http://dx.doi.org/10.1200/jco.2014.55.5094.
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Purpose To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC). Patients and Methods We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months). Results Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation–positive versus –negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation–positive versus –negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations. Conclusion Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.
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Bentz, Brandon G., Brian T. Miller, Joseph A. Holden, Leslie R. Rowe, and Joel S. Bentz. "B-RAF V600E mutational analysis of fine needle aspirates correlates with diagnosis of thyroid nodules." Otolaryngology–Head and Neck Surgery 140, no. 5 (May 2009): 709–14. http://dx.doi.org/10.1016/j.otohns.2009.01.007.
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Objective: A mutation of B-type RAF kinase (B-RAF) represents the most common genetic alteration in papillary thyroid cancer (PTC), possibly signifying a more aggressive biology. Fine needle aspiration (FNA) represents the most useful initial diagnostic tool of thyroid nodules. Molecular analysis of the mutation status of B-RAF in thyroid nodule FNAs may provide guidance for treatment planning. Study Design: Cross-sectional study. Subjects and Methods: A retrospective chart review was undertaken for clinically relevant data of papillary thyroid cancer (PTC), follicular variant of PTC (FV-PTC), and nonmalignant goiters. After blinded pathologic review, histologic and cytologic samples were analyzed by LightCycler PCR (LCPCR) with allele-specific fluorescent probe melting curve analysis (FMCA) for the V600E mutation of B-RAF. Results: Of the 45 patient samples analyzed, B-RAF mutation was found to be significantly higher in papillary carcinomas when compared to follicular variant of papillary thyroid carcinomas (55.6% vs 14.3%, P = 0.05). Pathologic B-RAF mutational status significantly correlated with cytologic B-RAF mutational status ( P < 0.0001), cytologic interpretation ( P = 0.012), and histologic diagnosis ( P = 0.011). Conclusions: Determination of B-RAF V600E mutation of thyroid nodule FNAs by LCPCR may be a useful tool to guide treatment planning. These data support investigating the utility of this molecular marker in a prospective manner.
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Nam, Myungwoo, Woojung Yang, Ju Young Lee, Jaeyoun Choi, Hansol Choi, Eugene Kim, Emma Yu, et al. "753 The immune landscape of papillary thyroid cancer and its association with neoantigen landscape and DNA repair gene mutations." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A801. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0753.
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BackgroundTumors with high tumor mutational burden (TMB) or defects in mismatch repair (dMMR) respond well to immune checkpoint inhibitors (ICIs).1 2 TMB and DNA repair gene mutations including dMMR are closely related to the increase of neoantigens, which are recognized by immune cells to trigger an immune response.1 3 Although not a standard of care in thyroid cancer treatment, there are ongoing clinical trials for ICI use in differentiated thyroid carcinoma. However, not much has been explored concerning the neoantigen landscape and its association with immune traits in papillary thyroid cancer (PTC). We aim to analyze the immune landscape of PTC in association with neoantigen burden, TMB, and DNA repair gene mutations.MethodsWe used the PTC cohort data from The Cancer Genome Atlas (TCGA). The mutation counts and data for neoantigen prediction were acquired from TCGA mutation calling. CloudNeo pipeline was used for neoantigen prediction. TMB was calculated as the sum of missense and indel mutation counts per megabase pairs covered by whole-exome sequencing. Tumor-infiltrating immune cells were estimated using CIBERSORT.ResultsOut of the 496 PTC patients from cBioPortal, a subset of 400 patients with available mutation counts and predicted neoantigen burden was included in the study. Immune cell infiltration estimated by CIBERSORT showed macrophage M2 as the most abundant, followed by macrophage M0 and other T cells (figure 1). The TMB ranged from 0.03 to 2.05 with a median value of 0.2. Neoantigen burden ranged from 0 to 18 with a median value of 1, which is relatively low compared to the median value of 18 in non-small cell lung cancer (NSCLC)1 (figure 2). One or more DNA repair gene mutations were discovered in 32 patients (8%). The mutation status of repair genes was not related to TMB or neoantigen burden. TMB or neoantigen burden was not related to immune traits such as infiltration of CD8+ T cells or regulatory T cells, cytolytic activity score, and PD-L1 expression.Abstract 753 Figure 1Immune cell infiltration estimated by CIBERSORTAbstract 753 Figure 2Histogram of neoantigen burdenConclusionsThis is the first study to report the immune landscape of PTC in the context of neoantigen. The lack of association between TMB or neoantigen burden with immune traits may be due to the relatively low number of neoantigens in PTC compared to other immunogenic cancers such as NSCLC. Our results suggest that mutations in DNA repair genes or TMB are likely to have limited value in predicting response to ICI treatment in PTC.ReferencesChae YK, et al., Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma. Sci Rep 2019; 9:3235.Rizvi NA, et al., Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348:124–128.Schumacher TN, Schreiber RD, Neoantigens in cancer immunotherapy. Science 2015; 348:69–74.
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Kim, Seo Ki, Jung-Woo Woo, Jun Ho Lee, Inhye Park, Jun-Ho Choe, Jung-Han Kim, and Jee Soo Kim. "Chronic lymphocytic thyroiditis and BRAF V600E in papillary thyroid carcinoma." Endocrine-Related Cancer 23, no. 1 (October 16, 2015): 27–34. http://dx.doi.org/10.1530/erc-15-0408.
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It has been reported that papillary thyroid carcinoma (PTC) with chronic lymphocytic thyroiditis (CLT) is less associated with extrathyroidal extension (ETE), advanced tumor stage and lymph node (LN) metastasis. Other studies have suggested that concurrent CLT could antagonize PTC progression, even in BRAF-positive patients. Since the clinical significance of the BRAF mutation has been particularly associated with conventional PTC, the purpose of this study was to determine the clinical significance of CLT according to BRAF mutation status in conventional PTC patients. We retrospectively reviewed the medical records of 3332 conventional PTC patients who underwent total thyroidectomy with bilateral central neck dissection at the Thyroid Cancer Center of Samsung Medical Center between January 2008 and June 2015. In this study, the prevalence of BRAF mutation was significantly less frequent in conventional PTC patients with CLT (76.9% vs 86.6%). CLT was an independent predictor for low prevalence of ETE in both BRAF-negative (OR=0.662, P=0.023) and BRAF-positive (OR=0.817, P=0.027) conventional PTC patients. In addition, CLT was an independent predictor for low prevalence of CLNM in both BRAF-negative (OR=0.675, P=0.044) and BRAF-positive (OR=0.817, P=0.030) conventional PTC patients. In conclusion, BRAF mutation was significantly less frequent in conventional PTC patients with CLT. However, CLT was an independent predictor for less aggressiveness in conventional PTC patients regardless of BRAF mutation status.
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Elisei, Rossella, Clara Ugolini, David Viola, Cristiana Lupi, Agnese Biagini, Riccardo Giannini, Cristina Romei, Paolo Miccoli, Aldo Pinchera, and Fulvio Basolo. "BRAFV600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study." Journal of Clinical Endocrinology & Metabolism 93, no. 10 (October 1, 2008): 3943–49. http://dx.doi.org/10.1210/jc.2008-0607.
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Background: The BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAFV600E mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAFV600E mutation in PTC patients with a long-term follow-up. Methods: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAFV600E mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAFV600E mutation, clinicopathological features, and outcome of PTC patients were evaluated. Results: The BRAFV600E mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAFV600E mutation (P < 0.002). However, at multivariate analysis only the BRAFV600E mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAFV600E-mutated group (P = 0.015). Conclusions: In this study the BRAFV600E mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAFV600E mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.
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Gąsior-Perczak, Danuta, Artur Kowalik, Krzysztof Gruszczyński, Agnieszka Walczyk, Monika Siołek, Iwona Pałyga, Sławomir Trepka, et al. "Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma." Cancers 13, no. 3 (January 26, 2021): 470. http://dx.doi.org/10.3390/cancers13030470.
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The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.
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Xing, Mingzhao, Ali S. Alzahrani, Kathryn A. Carson, Young Kee Shong, Tae Yong Kim, David Viola, Rossella Elisei, et al. "Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer." Journal of Clinical Oncology 33, no. 1 (January 1, 2015): 42–50. http://dx.doi.org/10.1200/jco.2014.56.8253.
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Purpose To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). Patients and Methods This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). Results The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation–positive and 11.6% (125 of 1,082) of BRAF V600E mutation–negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation–positive versus –negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation–positive versus –negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.
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Xing, Mingzhao, William H. Westra, Ralph P. Tufano, Yoram Cohen, Eli Rosenbaum, Kerry J. Rhoden, Kathryn A. Carson, et al. "BRAF Mutation Predicts a Poorer Clinical Prognosis for Papillary Thyroid Cancer." Journal of Clinical Endocrinology & Metabolism 90, no. 12 (December 1, 2005): 6373–79. http://dx.doi.org/10.1210/jc.2005-0987.
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Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Main Outcome Measure: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. Results: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3–29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1–14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. Conclusions: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.
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Sapio, Maria Rosaria, Daniela Posca, Giancarlo Troncone, Guido Pettinato, Lucio Palombini, Guido Rossi, Gianfranco Fenzi, and Mario Vitale. "Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA)." European Journal of Endocrinology 154, no. 2 (February 2006): 341–48. http://dx.doi.org/10.1530/eje.1.02072.
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Objective: The somatic point mutation in the BRAF gene, which results in a valine-to-glutamate substitution at residue 600 (BRAFV600E), is an ideal hallmark of papillary thyroid carcinoma (PTC). However, its prevalence is varyingly reported in different studies, and its expression in the follicular variant PTC is controversial, reducing its potential usefulness as diagnostic marker. Design and methods: We developed an assay based on mutant allele-specific PCR amplification (MASA) to detect BRAF mutation. We compared the sensitivity of MASA, single-strand conformation polymorphism (SSCP) and direct DNA sequencing of PCR products. Then, we used MASA 78 to analyze 78 archival thyroid tissues, including normal samples, follicular adenomas, follicular carcinomas and PTC. Results: The MASA assay proved to be a more sensitive method than SSCP and DNA sequencing of PCR products. BRAF mutation was found by MASA in 19/43 (44.2%) of PTC, including 14/31 (45.2%) classic forms and 5/12 (41.7%) follicular variants. No mutations of BRAF were detected in the normal thyroid tissues, nor in follicular adenomas or follicular carcinomas. No correlation was found between BRAF mutation and clinicopathologic features nor with recurrence during a postoperative follow-up period of 4–11 years. BRAFV600E significantly correlated with absence of node metastasis. Conclusions: BRAFV600E is present in PTC, both in the classic form and in follicular variant with similar prevalence. No correlation was found between BRAF mutation and aggressive clinical behavior. MASA-PCR proved to be a specific, sensitive and reliable method to detect BRAF T1799A in DNA extracted from different sources, including cytologic samples obtained either fresh or from archival glass slides. We propose this method as a useful tool to improve accuracy of preoperative diagnosis identifying PTC from biopsies with indeterminate cytologic findings.
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Zatelli, Maria Chiara, Giorgio Trasforini, Stefania Leoni, Gemma Frigato, Mattia Buratto, Federico Tagliati, Roberta Rossi, Luigi Cavazzini, Elio Roti, and Ettore C. degli Uberti. "BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine-needle aspiration biopsies." European Journal of Endocrinology 161, no. 3 (September 2009): 467–73. http://dx.doi.org/10.1530/eje-09-0353.
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ObjectivePapillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid cancers, presenting the V600E activating BRAF mutation in 29–83% of cases. The aim of our study is to analyze the influence of BRAF mutation analysis on the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) in patients with suspected PTC.Design and methodsThyroid cytoaspirates from 469 nodules (size: 1.1±0.8 cm) with ultrasonographic features suspicious of malignant lesion, performed in 374 patients, were submitted to cytological evaluation and to biomolecular analysis, carried out after somatic DNA isolation, specific PCR amplification, and subsequent automated direct sequencing. All PCR fragments were also processed by specific enzyme restriction analysis.ResultsBRAF V600E mutation was found in 48 samples, 41 of which were also cytologically diagnosed as PTC, with histologic confirmation after thyroidectomy. Total thyroidectomy was perfomed also in seven patients with negative cytology but positive BRAF mutation, with histological confirmation of PTC in all. Among the 429 BRAF-negative samples, 407 had negative cytology for PTC, while 22 were diagnosed as suspected PTC and underwent total thyroidectomy with histological diagnosis of PTC in 17 and benign lesion in five. The prevalence of BRAF V600E mutation among histologically diagnosed PTC patients was 64%. Biomolecular analysis significantly increased cytology sensitivity for PTC from 77.3 to 86.7% (P<0.01).ConclusionsThese data indicate that BRAF V600E mutation analysis can significantly improve FNAB diagnostic accuracy. However, biomolecular analysis is complementary to cytology, which should always be performed.
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Li, Ruoxuan, Jiping Hao, Zhao Zhu, Xudong Qiao, Ling Wang, and Zubang Zhou. "Correlation between US-FNAC with BRAF V600E Mutation Analysis and Central Neck Lymph Node Metastasis in cN0 Papillary Thyroid Cancer." BioMed Research International 2021 (July 1, 2021): 1–6. http://dx.doi.org/10.1155/2021/9937742.
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The aim of this study was to explore the correlation between ultrasound-guided fine-needle aspiration cytology(US-FNAC) combined with BRAF V600E mutation analysis and central neck lymph node metastasis in cN0 papillary thyroid cancer, so as to provide reliable molecular evidence to use it for preoperative evaluation, operation procedure design, and postoperative follow-up planning in clinic. Specimens were obtained from 250 patients with cN0 thyroid cancer (TI-RADS≥4a, highly suspected of PTC by US-FNAC) after bilateral thyroidectomy and central neck lymph node dissection with accessible postoperative pathologic results of PTC and central neck lymph nodes and used for cytological diagnosis by H&E stain and BRAF V600E mutation detection. Single-factor analysis showed that differences between the central neck lymph node metastasis and nonmetastasis groups were statistically significant in gender, BRAF V600E mutation, and extracapsular extension. Logistic multivariate regression analysis showed significant differences in gender, BRAF V600E mutation, and extracapsular extension. Positive BRAF V600E mutations by US-FNAC, extracapsular extension, and male gender are risk factors of central neck lymph node metastasis in cN0 PTC metastatic PTC to central neck lymph node. Patients with those factors should undergo prophylactic central neck lymph node dissection.
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Kim, Min Jhi, Jin Kyong Kim, Gi Jeong Kim, Sang-Wook Kang, Jandee Lee, Jong Ju Jeong, Woong Youn Chung, Daham Kim, and Kee-Hyun Nam. "TERT Promoter and BRAF V600E Mutations in Papillary Thyroid Cancer: A Single-Institution Experience in Korea." Cancers 14, no. 19 (October 8, 2022): 4928. http://dx.doi.org/10.3390/cancers14194928.
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Telomerase reverse transcriptase (TERT) promoter mutation has been investigated for its clinical and prognostic significance in aggressive papillary thyroid cancer (PTC). In this study, we aimed to assess the prevalence, clinicopathologic features, and treatment outcomes of TERT mutation-positive PTCs along with the common BRAF V600E mutation. We performed mutational analyses for BRAF and the TERT promoter in thyroid cancer patients who had undergone surgery at our institution since 2019. We reviewed and analyzed 7797 patients with PTC in this study. The prevalence of BRAF V600E and TERT promoter mutations was 84.0% and 1.1%, respectively. Multifocal gene mutations in bilateral PTCs were identified. TERT promoter mutations were associated with older age, larger tumor size, tumor multifocality, tumor variants, advanced stages, more adjuvant radioactive iodine treatment (RAI), higher stimulated serum thyroglobulin level before RAI, and more uptakes in the regions outside the surgical field on a post-RAI whole-body scan. The coexistence of BRAF V600E and TERT promoter mutations exacerbated all clinicopathologic characteristics. The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.
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Liu, Dingxie, Zhi Liu, Stephen Condouris, and Mingzhao Xing. "BRAF V600E Maintains Proliferation, Transformation, and Tumorigenicity of BRAF-Mutant Papillary Thyroid Cancer Cells." Journal of Clinical Endocrinology & Metabolism 92, no. 6 (June 1, 2007): 2264–71. http://dx.doi.org/10.1210/jc.2006-1613.
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Abstract Context: Although the BRAF V600E mutant can initiate the formation of papillary thyroid cancer (PTC), it is unclear whether it is required to maintain cell proliferation, transformation, and tumor growth of BRAF mutation-harboring PTC. Objective: The aim of the study was to investigate whether BRAF V600E is required for the proliferation, transformation, and tumorigenicity of BRAF mutation-harboring PTC cells. Design: We addressed this issue using BRAF small interference RNA (siRNA) to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. Results: PTC cell proliferation and transformation were suppressed in specific BRAF siRNA clones, but not in control scrambled siRNA clones. Specifically, taking the advantage of stable BRAF knockdown, we were able to show continued suppression of PTC cell proliferation and transformation, or anchorage-independent colony formation in soft agar, after long-term culture. Moreover, we also demonstrated that in vivo tumorigenicity and growth of tumors from the specific BRAF siRNA cell clones in nude mice were suppressed compared with control clones. Conclusions: BRAF V600E is not only an initiator of PTC as demonstrated previously but is also a maintainer of proliferation, transformation, and tumorigenicity of PTC cells harboring BRAF mutation, and growth of tumors derived from such cells continues to depend on BRAF V600E. These results provide further support for potentially effective therapy targeted at BRAF for BRAF mutation-harboring PTC.
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Hińcza, Kinga, Artur Kowalik, Iwona Pałyga, Agnieszka Walczyk, Danuta Gąsior-Perczak, Estera Mikina, Tomasz Trybek, et al. "Does the TT Variant of the rs966423 Polymorphism in DIRC3 Affect the Stage and Clinical Course of Papillary Thyroid Cancer?" Cancers 12, no. 2 (February 12, 2020): 423. http://dx.doi.org/10.3390/cancers12020423.
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Thyroid cancer (TC) is the most common cancer of the endocrine system. Most new diagnoses are of low-grade papillary thyroid cancer (PTC), suggesting that PTC may be over-diagnosed. However, the incidence of advanced-stage PTC has increased in recent years. It is therefore very important to identify prognostic factors for advanced PTC. Somatic mutation of the BRAF gene at V600E, or the coexistence of the BRAF V600E mutation and mutations in the TERT promoter are associated with more aggressive disease. It would also be valuable to identify genetic risk factors affecting PTC prognosis. We therefore evaluated the impact of the rs966423 polymorphism in the DIRC3 gene, including its relationship with unfavorable histopathological and clinical features and mortality, in differentiated thyroid cancer (DTC). The study included 1466 patients diagnosed with DTC from one center. There was no significant association between the DIRC3 genotype at rs966423 (CC, CT, or TT) and any histopathological or clinic factor examined, including initial response to therapy, response at follow-up, or overall mortality, in DTC patients.
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M S, Bhuvitha, and Krishna G. "BRAFV600E Mutation in Papillary Carcinoma Thyroid." Annals of Pathology and Laboratory Medicine 9, no. 6 (July 9, 2022): A102–108. http://dx.doi.org/10.21276/apalm.3167.
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Background: Thyroid malignancies comprise 1 % of total human malignancies, Papillary Thyroid Carcinoma (PTC) is the most common malignant tumour of thyroid cancers. It is estimated that 80 % of thyroid malignancies are comprised of papillary carcinoma thyroid, which shows increased incidence in women. The most important etiology of PTC is mutation of RET/RAS/BRAF which activates MAPK signaling pathway. The BRAF V600E activating point mutation appears to be highly specific for PTC.
Methods: It is cross sectional study of 56 cases studied in the Government Medical college, Thiruvananthapuram, Kerala. Consecutive cases of histo-pathologically proven cases were selected and Immunohistochemical (IHC) studies for BRAFV600E were conducted, and results were recorded.
Result: Our study showed female preponderance and equal distribution of cases above and below 45 years of age. Size of the primary tumour was more than 1cm for majority of cases. In our study out of 56 cases studied 45 patients showed BRAFV600E expression comprising of 80% positivity. A 44% of the total cases studied showed lymph node metastasis.
Conclusion: We conclude in our study that BRAFV600E mutation is most common mutation in primary PTC patients. BRAFV600E expression most seen in elderly patients and shows strong association with lymph node metastasis. IHC assay is a reliable method to detect BRAFV600E mutation in PTC and can be used as alternative to molecular methods on routine practice
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Kocsis-Deák, Barbara, Kristóf Árvai, Bernadett Balla, Bálint Tóbiás, Andrea Kohánka, Balázs Járay, János Horányi, et al. "Targeted Mutational Profiling and a Powerful Risk Score as Additional Tools for the Diagnosis of Papillary Thyroid Cancer." Pathology & Oncology Research 26, no. 1 (November 22, 2019): 101–8. http://dx.doi.org/10.1007/s12253-019-00772-4.
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AbstractNowadays, the complementary diagnostics based on the suspicious thyroid lesion specific mutational state analysis is indispensable in the clinical practice. We aimed to test and validate our novel 568-mutational hotspot panel (23 cancer-related genes) on papillary thyroid cancers (PTCs) and their tumor-free pairs to find the most powerful mutation pattern related to PTC. The sequencing method was carried on with Ion Torrent PGM on 67 thyroid tissue samples. The most commonly detected mutation was the BRAF c.1799 T > A in all non-classical PTC cases. We utilized a multivariate statistical method (CVA) to determine a discrimination score based on mutational data array and to assess malignancy risk. Based on variants, the BRAF gene has by far the highest indicative power, followed by TSHR and APC. We highlighted novel aspects of the mutational profile and genetic markers of PTC. CVA has correctly assigned most of the samples based on the mutation frequencies and different variables of the selected genes, with high analytical probabilities. The final goal is to set up a new comprehensive rule-in and rule-out test to support the clinical decision making mainly in inconclusive fine-needle aspiration biopsy cases.
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Rasquin, Lorena, Janna Prater, Jane Mayrin, and Corrado Minimo. "Simultaneous Pheochromocytoma, Paraganglioma, and Papillary Thyroid Carcinoma without Known Mutation." Case Reports in Endocrinology 2018 (October 14, 2018): 1–3. http://dx.doi.org/10.1155/2018/6358485.
Full textAbstract:
Background. Pheochromocytoma/paraganglioma is a rare tumor from neuroendocrine cells. 1/3rd of cases have germline mutations. Papillary thyroid carcinoma (PTC) is a common neoplasm from follicular cells of the thyroid. We report a case of pheochromocytoma/paraganglioma and PTC with negative testing for common mutations. Case. 32-year-old male with incidental liver mass during laparoscopy for acute appendicitis. His symptoms included abdominal pain and profuse axillary hyperhidrosis. MRI showed an 11x12x14 cm cystic and solid mass in right adrenal gland, and 3.4x2.9x3.8 cm mass in porta hepatis. Urine metanephrines was elevated. After preoperative alpha-blockade, patient underwent total right adrenalectomy. Pathology report confirmed diagnosis of pheochromocytoma. According to the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP), tumor’s score was 9, indicating poorly differentiated tumor. Ki67 index 5% and S100 were negative. Postoperatively, plasma free metanephrines normalized but plasma free normetanephrines remained elevated. Based on this biochemical profile, presence of paraganglioma was suspected. CT showed 4.2x3.5 cm round soft tissue mass in porta hepatis which increased in size from previous MRI. Simultaneously, PET scan identified a 1.5 cm thyroid mass. Calcitonin level was normal. Fine-needle aspiration was consistent with PTC. Resection of the mass and total thyroidectomy were performed with confirmation of paraganglioma S100 positive and PTC. Normetanephrines decreased to 283 (<148 pg/mL); free metanephrines remained normal. Gene mutation of EGLN1, FH, KIF1B, MEN1, NF1, RET, SDHAF2, SDHC, SDHD, TMEM127, VHL, and SDHA was negative. Conclusion. Whether paraganglioma/pheochromocytoma/PTC combination is coincidental or resulted from an underlying unknown mutation cannot be excluded.
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Zhang, Junru. "BRAF gene mutation and papillary thyroid carcinoma." Highlights in Science, Engineering and Technology 14 (September 29, 2022): 134–43. http://dx.doi.org/10.54097/hset.v14i.1602.
Full textAbstract:
Nowadays, Thyroid carcinoma (TC) is the most common malignant tumor of endocrine system, accounting for about 1% of the malignant tumors in the whole body, ranking first in the head and neck malignant tumors. Papillary thyroid carcinoma (PTC) is a malignant tumor originated from thyroid follicular epithelial cells, which is the most common pathological type in TC. V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a molecular biological marker for the diagnosis and prognosis of PTC and a target gene for the treatment of PTC. Its gene mutation is a hot point in the TC research field. The most common gene mutation is BRAF V600E mutation and it is a molecular marker in PTC. With the deep-going of its research, contradictions and controversies about the relationship between BRAF V600E and PTC gradually emerge. Many molecular targeted drugs targeting BRAF gene are also being continuously researched and some achievements have been made. This review mainly expounds the relationship between BRAF V600E and clinicopathological features, analyzes and expounds the controversial parts currently as well as show the research status of molecular targeted drugs.
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Zhu, Guoquan, Yuying Deng, Liqin Pan, Wei Ouyang, Huijuan Feng, Juqing Wu, Pan Chen, Jing Wang, Yanying Chen, and Jiaxin Luo. "Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy." Endocrine Connections 8, no. 6 (June 2019): 754–63. http://dx.doi.org/10.1530/ec-19-0045.
Full textAbstract:
The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014–December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012–1.039, P < 0.001; OR = 1.685, 95% CI = 1.213–2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.