Publications by authors named "Mingzhao Xing"

139 Publications

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

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) cascade plays a critical role in the regulation of mutant , in which FOS acts as a transcriptional factor for to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 () and inactivation of two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of up-regulating its expression. Thus, this study identifies a therapeutic strategy for promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.
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http://dx.doi.org/10.1073/pnas.2022779118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980366PMC
March 2021

Reply to Delanghe, Boudin and Daniele.

Clin Infect Dis 2020 Sep 28. Epub 2020 Sep 28.

School of Medicine, The Southern University of Science and Technology, Shenzhen, People's Republic of China.

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http://dx.doi.org/10.1093/cid/ciaa1477DOI Listing
September 2020

Relationship between the ABO Blood Group and the COVID-19 Susceptibility.

Clin Infect Dis 2020 Aug 4. Epub 2020 Aug 4.

School of Medicine, The Southern University of Science and Technology, Shenzhen, People's Republic of China.

To explore any relationship between the ABO blood group and the COVID-19 susceptibility, we compared ABO blood group distributions in 2,173 COVID-19 patients with local control populations, and found that blood group A was associated with an increased risk of infection, whereas group O was associated with a decreased risk.
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http://dx.doi.org/10.1093/cid/ciaa1150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454371PMC
August 2020

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

Proc Natl Acad Sci U S A 2020 07 19;117(27):15846-15851. Epub 2020 Jun 19.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21827;

Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring  V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both V600E and  promoter mutations but had little proapoptotic effect in cells harboring only  V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only  V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on  V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only  V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high- expression. promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of V600E and  promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.
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http://dx.doi.org/10.1073/pnas.2004707117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355024PMC
July 2020

Early Virus Clearance and Delayed Antibody Response in a Case of Coronavirus Disease 2019 (COVID-19) With a History of Coinfection With Human Immunodeficiency Virus Type 1 and Hepatitis C Virus.

Clin Infect Dis 2020 11;71(16):2233-2235

Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China.

The effect of host immune status on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. Here, we report the first case of coronavirus disease 2019 (COVID-19) with human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus coinfection, who showed a persistently negative SARS-CoV-2 RNA test but delayed antibody response in the plasma. This case highlights the influence of HIV-1-induced immune dysfunction on early SARS-CoV-2 clearance.
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http://dx.doi.org/10.1093/cid/ciaa408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184426PMC
November 2020

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

Eur J Cancer 2020 01 29;124:161-169. Epub 2019 Nov 29.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management.

Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months).

Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC.

Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.
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http://dx.doi.org/10.1016/j.ejca.2019.10.017DOI Listing
January 2020

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

PLoS One 2019 23;14(10):e0221093. Epub 2019 Oct 23.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Previous studies have documented an intrinsic association between breast cancer (BC) and thyroid cancer (TC), but the clinical relevance of this relationship is not well defined. In the present study, we specifically investigated the impact of a history of TC on clinical outcomes of BC. We performed a population-based comparative analysis of tumor behaviors and BC-specific mortalities in 427,893 female patients with BC in the USA Surveillance, Epidemiology and End Results 9 database (1973-2013). In this cohort of subjects, 2,569 patients also had a history of differentiated TC (BC/TC), including BC diagnosed before TC (BC-1st) and BC diagnosed after TC (TC-1st), with the median follow-up time of 81 (IQR, 33-160) months. We found that, compared with matched BC-only patients, less aggressive BC tumor behaviors occurred in BC/TC patients, as exemplified by a distant metastasis rate of 7.0% in the former versus 3.3% in the latter (P<0.001). In BC/TC, BC-1st, and TC-1st patients versus their matched BC-only patients, BC-specific mortalities were 11.3% versus 21.0%, 9.9% versus 26.4%, and 12.4% versus 16.9%. These corresponded to hazard ratios (HR) (95% CI) of 0.47 (0.42-0.53), 0.31 (0.26-0.37), and 0.72 (0.61-0.84), respectively (all P<0.001), being lowest in BC-1st patients <50 years old [HR = 0.22 (0.16-0.31)], which remained significant after adjustment for clinicopathological and socioeconomic factors. Estrogen/progesterone receptor expression in BC tumors was significantly higher in patients with BC/TC than matched BC-only patients, providing evidence that BC in the former was biologically unique. Thus, a history of TC, particularly in younger BC-1st patients, may identify BC as a unique disease entity characterized by a decreased disease-specific mortality risk. The results have potentially important clinical and biological implications for BC in this special patient population and encourage further studies to confirm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221093PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808426PMC
March 2020

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

J Nucl Med 2020 02 2;61(2):177-182. Epub 2019 Aug 2.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and

V600E and promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes. This study investigated the role of mutation patterns in loss of RAI avidity in recurrent PTC. This was a retrospective study of the relationship between loss of RAI avidity in structural recurrent PTC and the genotype patterns of V600E and promoter mutations in 164 patients (104 women and 60 men) with a median age of 50 y (interquartile range, 35-62 y). The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When the cohort was divided into mutation and wild-type groups, the RAI avidity loss was 80.4% versus 33.9% ( < 0.001) in V600E versus wild-type patients, with an adjusted odds ratio of 7.11 (95% confidence interval [CI], 3.24-16.27), and 89.4% versus 52.1% ( < 0.001) in mutation versus wild-type patients, with an adjusted odds ratio of 6.89 (95% CI, 2.28-25.66). When the cohort was divided into 4 genotypes, the RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with V600E alone, mutation alone, and the genetic duet of coexisting and mutations, versus 30.2% (16/53) in patients with neither mutation ( < 0.001, = 0.251, and < 0.001, respectively). These corresponded to odds ratios of 5.39 (95% CI, 2.31-13.13), 2.84 (95% CI, 0.53-16.32), and 81.04 (95% CI, 11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; = 0.019) between V600E and mutation in cooperatively affecting RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. V600E alone and, particularly, coexisting V600E and promoter mutations are strongly associated with loss of RAI avidity and impairment of the iodide-metabolizing machinery in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC.
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http://dx.doi.org/10.2967/jnumed.119.227652DOI Listing
February 2020

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

J Clin Endocrinol Metab 2019 11;104(11):4941-4948

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: The mortality risk of stage II differentiated thyroid cancer (DTC) based on the American Joint Committee on Cancer (AJCC) staging system requires further investigation.

Methods: Retrospective study of DTC in the US Surveillance, Epidemiology, and End Results program for disease-specific mortality risk in various AJCC stages, with patient age stratification of stage II disease.

Results: Using AJCC staging system 6.0, hazard ratios (HRs) of mortality for stage II DTC in patients <45 yo and patients ≥45 yo and stages III, IVA, IVB, and IVC compared with stage I were 46.95, 4.95, 9.82, 57.37, 222.10, and 468.68, respectively, showing a robustly higher mortality risk in stage II disease in patients <45 yo than in older patients (P < 0.001), comparable with stage IVA (P = 0.482). Similar results were obtained with AJCC 7.0. With AJCC 8.0, HRs of mortality for stage II in patients <55 yo and patients ≥55 yo and stages III, IVA, and IVB compared with stage I were 75.16, 11.23, 69.45, 134.94, and 235.70, respectively, showing a robustly higher risk in stage II disease in patients <55 yo than in older patients (P < 0.001), comparable with stage III (P = 0.57). Kaplan-Meier survival curves displayed a sharp decline with stage II disease in patients <45/55 yo compared with older patients.

Conclusions: The mortality risk of stage II DTC was sharply differentiated at patient age 45/55 years, being robustly high in younger patients and comparable with stage III/IVA. This emphasizes the importance of considering age when managing stage II DTC and not treating it as a uniformly low-risk disease.
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http://dx.doi.org/10.1210/jc.2018-02809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453036PMC
November 2019

Identification and characterization of two novel oncogenic mTOR mutations.

Oncogene 2019 06 27;38(26):5211-5226. Epub 2019 Mar 27.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Mammalian target of rapamycin (mTOR) signaling is often aberrantly activated, particularly when genetically altered, in human cancers. mTOR inhibitors targeting the activated mTOR signaling are highly promising anti-cancer drugs. Knowing the activating genetic change in mTOR can help guide the use of mTOR inhibitors for cancer treatment. This study was conducted to identify and characterize novel oncogenic mTOR mutations that can potentially be therapeutic targets in human cancer. We sequenced 30 exons of the mTOR gene in 12 thyroid cancer cell lines, 3 melanoma cell lines, 20 anaplastic thyroid cancer (ATC) tumors, and 23 melanoma tumors and functionally characterized the identified novel mTOR mutations in vitro and in vivo. We identified a novel point mutation A1256G in ATC cell line and G7076A in melanoma tumor in exon 9 and exon 51 of the mTOR gene, respectively. Over-expression of the corresponding mTOR mutants H419R and G2359E created through induced mutagenesis showed markedly elevated protein kinase activities associated with the activation of mTOR/p70S6K signaling in HEK293T cells. Stable expression of the two mTOR mutants in NIH3T3 cells strongly activated the mTOR/p70S6K signaling pathway and induced morphologic transformation, cell focus formation, anchorage-independent cell growth, and invasion. Inoculation of these mutant-expressing cells in athymic nude mice induced rapid tumor development, showing their driving oncogenicity. We also demonstrated that transfection with the novel mutants conferred cells high sensitivities to the mTOR inhibitor temsirolimus. We speculate that human cancers harboring these mTOR mutations, such as ATC and melanoma, may be effectively treated with inhibitors targeting mTOR.
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http://dx.doi.org/10.1038/s41388-019-0787-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597304PMC
June 2019

Entering an Era of Precision Management of Thyroid Cancer.

Authors:
Mingzhao Xing

Endocrinol Metab Clin North Am 2019 03;48(1):xvii-xviii

School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21207, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2018.12.001DOI Listing
March 2019

Genetic-guided Risk Assessment and Management of Thyroid Cancer.

Authors:
Mingzhao Xing

Endocrinol Metab Clin North Am 2019 03;48(1):109-124

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287, USA. Electronic address:

Controversies exist on how to optimally manage thyroid cancer because the prognosis is often uncertain based on clinical backgrounds. This can now be helped with prognostic genetic markers in thyroid cancer, exemplified by BRAF V600E and TERT promoter mutations, which have been well characterized and widely appreciated. The genetic duet of BRAF V600E/RAS and TERT promoter mutations is a most robust prognostic genetic pattern for poor prognosis of differentiated thyroid cancer. The high negative predictive values of the prognostic genetic markers are equally valuable. The best prognostic value of genetic markers in thyroid cancer is achieved through a clinical risk level-based and genotype-individualized manner.
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http://dx.doi.org/10.1016/j.ecl.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447365PMC
March 2019

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

J Clin Oncol 2018 09 2;36(27):2787-2795. Epub 2018 Aug 2.

Fei Wang, Shihua Zhao, and Yangang Wang, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Fei Wang, Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto Auxologico Italiano, Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Institute Oncology Center, Gliwice, Poland; Alfred K. Lam, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols" and Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
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http://dx.doi.org/10.1200/JCO.2018.78.5097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145834PMC
September 2018

Reply to M. Melo et al.

J Clin Oncol 2018 05 23;36(14):1457-1458. Epub 2018 Mar 23.

Xiaopei Shen and Mingzhao Xing, The Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1200/JCO.2018.78.2169DOI Listing
May 2018

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

Nat Commun 2018 02 8;9(1):579. Epub 2018 Feb 8.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression. Elevated TERT functions as a strong oncoprotein, robustly promoting aggressive behaviors of cancer cells and tumor development. We thus identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of GABPB promoter plays a key role in functionally bridging the two oncogenes in cooperatively promoting oncogenesis, providing important cancer biological and clinical implications.
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http://dx.doi.org/10.1038/s41467-018-03033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805723PMC
February 2018

Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer.

J Clin Oncol 2018 02 14;36(5):438-445. Epub 2017 Dec 14.

Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; Alfred K. Lam, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, The University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh School of Medicine, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Ciberonc, Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
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http://dx.doi.org/10.1200/JCO.2017.74.5497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807010PMC
February 2018

BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment.

J Natl Cancer Inst 2018 04;110(4):362-370

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.

Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.

Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.

Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
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http://dx.doi.org/10.1093/jnci/djx227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658860PMC
April 2018

When Somatic Mutations Are Associated With a Higher Aggressive Behavior-Reply.

JAMA Oncol 2017 10;3(10):1428-1429

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jamaoncol.2017.1513DOI Listing
October 2017

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer.

J Clin Endocrinol Metab 2017 09;102(9):3241-3250

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.

Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC.

Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation.

Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database.

Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.
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http://dx.doi.org/10.1210/jc.2017-00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587077PMC
September 2017

Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population.

Oncotarget 2017 Jan;8(5):8707-8716

Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Objective: Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population.

Methods: We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO).

Results: Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8.

Conclusion: We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.
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http://dx.doi.org/10.18632/oncotarget.14419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352434PMC
January 2017

A six-genotype genetic prognostic model for papillary thyroid cancer.

Endocr Relat Cancer 2017 01 14;24(1):41-52. Epub 2016 Nov 14.

Laboratory for Cellular and Molecular Thyroid ResearchDivision of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

A unique prognostic role of the genetic duet of BRAF V600E and TERT promoter mutations in papillary thyroid cancer (PTC) has been recently established, but the role of RAS mutation in this genetic interplay remains to be established. Using The Cancer Genome Atlas (TCGA) data of patients with PTC from 19 medical centers, we investigated the interactions among the three mutations in clinical outcomes of PTC. We found that BRAF and RAS mutations were mutually exclusive, but both were associated with TERT promoter mutations, with the genetic duet of BRAF/RAS and TERT mutations occurring in 34/388 (8.76%) patients. BRAF/RAS or TERT mutation had no or minimal effect alone, whereas coexisting BRAF/RAS and TERT mutations had a robust synergistic effect on poor clinicopathologic outcomes of PTC, including disease recurrence and patient mortality. For example, PTC recurrence rate was 52% with coexisting BRAF V600E/RAS and TERT promoter mutations vs 6.9% with no mutation, corresponding to a HR of 8.17 (95% CI 3.09-21.58), which remained significant at 14.71 (95% CI 2.79-77.61) after adjustment for clinicopathologic factors and institution. BRAF/RAS mutation or TERT mutation alone minimally affected Kaplan-Meier patient survival curves, whereas the genetic duet was associated with a sharp curve decline. Thus, by confirming and expanding previous findings in single-institution studies, this multicenter data analysis establishes a six-genotype genetic prognostic model for poor outcomes of PTC with a risk order of genetic duet of BRAF V600E/RAS mutation and TERT mutation >BRAF V600E = TERT mutation alone >RAS mutation alone = wild-type genes.
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http://dx.doi.org/10.1530/ERC-16-0402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132178PMC
January 2017

Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness.

Oncotarget 2017 Jan;8(1):900-914

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5'-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer.
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http://dx.doi.org/10.18632/oncotarget.13400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352205PMC
January 2017

Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer: Genetic Duet of BRAF and TERT Promoter Mutations in Thyroid Cancer Mortality.

JAMA Oncol 2017 Feb;3(2):202-208

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established.

Objective: To establish the prognostic power of this genetic duet in PTC-specific mortality.

Design, Setting, And Participants: This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1,295,228C>T and chr5:1,295,250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years).

Main Outcomes And Measures: BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC.

Results: Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation; 7 of 292 (2.4%) with BRAF V600E alone; 4 of 64 (6.3%) with TERT promoter mutation alone; and 15 of 66 (22.7%) with the genetic duet; and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95% CI, 0.30-2.13), 3.08 (95% CI, 1.47-6.46), 6.62 (95% CI, 2.48-17.64), and 29.86 (95% CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95% CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone; 8.18 (2.04-32.75) with TERT mutation alone; and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34; 95% CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46; 95% CI, 12.26-241.82), which remained strongly significant (HR, 18.56; 95% CI, 2.97-116.18) after adjustment for clinicopathological factors.

Conclusions And Relevance: These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.
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http://dx.doi.org/10.1001/jamaoncol.2016.3288DOI Listing
February 2017

Significance of the BRAF mRNA Expression Level in Papillary Thyroid Carcinoma: An Analysis of The Cancer Genome Atlas Data.

PLoS One 2016 13;11(7):e0159235. Epub 2016 Jul 13.

Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.

Background: BRAFV600E is the most common mutation in papillary thyroid carcinoma (PTC), and it is associated with high-risk prognostic factors. However, the significance of the BRAF mRNA level in PTC remains unknown. We evaluated the significance of BRAF mRNA expression level by analyzing PTC data from The Cancer Genome Atlas (TCGA) database.

Methods: Data from 499 patients were downloaded from the TCGA database. After excluding other PTC variants, we selected 353 cases of classic PTC, including 193 cases with BRAFV600E and 160 cases with the wild-type BRAF. mRNA abundances were measured using RNA-Seq with the Expectation Maximization algorithm.

Results: The mean BRAF mRNA level was significantly higher in BRAFV600E patients than in patients with wild-type BRAF (197.6 vs. 179.3, p = 0.031). In wild-type BRAF patients, the mean BRAF mRNA level was higher in cases with a tumor > 2 cm than those with a tumor ≤ 2.0 cm (189.4 vs. 163.8, p = 0.046), and was also higher in cases with lymph node metastasis than in those without lymph node metastasis (188.5 vs. 157.9, p = 0.040). Within BRAFV600E patients, higher BRAF mRNA expression was associated with extrathyroidal extension (186.4 vs. 216.4, p = 0.001) and higher T stage (188.1 vs. 210.2, p = 0.016).

Conclusions: A higher BRAF mRNA expression level was associated with tumor aggressiveness in classic PTC regardless of BRAF mutational status. Evaluation of BRAF mRNA level may be helpful in prognostic risk stratification of PTC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159235PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943731PMC
August 2017

Response.

J Natl Cancer Inst 2016 08 6;108(8). Epub 2016 May 6.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (TZ, XS, MX)

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http://dx.doi.org/10.1093/jnci/djw124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017927PMC
August 2016

BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients.

Oncotarget 2016 Apr;7(14):18346-55

Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China.

The role of telomerase reverse transcriptase (TERT) gene promoter mutations in the aggressiveness of papillary thyroid cancer (PTC) remains to be further investigated. Here we examined the relationship of TERT promoter mutations and BRAF V600E with the clinicopathological features of PTC in 653 patients. Sanger sequencing of genomic DNA from primary PTC tumors was performed for mutation detection and genotype-clinicopathological correlation of the tumor was analyzed. BRAF V600E and TERT promoter mutations were found in 63.7% (416 of 653) and 4.1% (27 of 653) of patients, respectively; the latter became 9.8% when only tumors ≥ 1.5 cm were analyzed. TERT promoter mutations occurred more frequently in BRAF mutation-positive cases compared to wild-type cases, being 5.3% in the former versus 2.1% in the latter (P = 0.050). BRAF and TERT promoter mutations were each significantly associated with high-risk clinicopathological features of PTC, such as old patient age, large tumor size, extrathyroidal invasion, capsular invasion, and advanced disease stages. Coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, as exemplified by extrathyroidal invasion seen in 54.5% (12/22) of patients harboring both mutations versus 9.9% (23/232) of patients harboring neither mutation (P < 0.001). Thus, this study, the largest on TERT mutation so far, demonstrates a significant role of BRAF V600E and TERT promoter mutations in the aggressiveness of PTC, which is particularly robust and cooperative when the two mutations coexist. These results, together with previous studies, establish a significant role of these mutations in the aggressiveness of PTC.
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http://dx.doi.org/10.18632/oncotarget.7811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951292PMC
April 2016

Recent incidences and differential trends of thyroid cancer in the USA.

Endocr Relat Cancer 2016 Apr 25;23(4):313-22. Epub 2016 Feb 25.

Laboratory for Cellular and Molecular Thyroid ResearchDivision of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Maryland, MD, USA

The incidence rate of thyroid cancer has been rising rapidly in recent decades; however, its trend remains unclear. To investigate this, we analyzed the database of the Surveillance, Epidemiology and End Results (SEER) 13, 1992-2012 in the USA, particularly focusing on conventional papillary thyroid cancer (CPTC) and follicular variant of PTC (FVPTC). Of the 75,992 thyroid cancers, 61.3% were CPTC and 25.7% were FVPTC, and their incidence rates (IRs) were significantly increased from 1992 to 2012 (P all < 0.001), with CPTC being 2.4 times of FVPTC (P < 0.001) and the overall average annual percent change (AAPC) of incidence being 6.3% in the former and 5.3% in the latter. IRs were increased in all thyroid cancers, albeit most dramatically in PTC, in virtually all ethnic/demographic groups in recent two decades; however, the incidence trends varied among different thyroid cancers, particularly differentiable between CPTC and FVPTC. For example, Joinpoint analyses revealed that the APC of CPTC before 1996 was 1.5% (P > 0.05), which jumped to 6.8% (P < 0.05) after 1996, whereas the APC of FVPTC before 2000 was 6.6% (P < 0.05), which dropped to 4.8% (P < 0.05) after 2000. IRs and incidence trends of PTC were uneven among different ethnic/demographic groups, as exemplified by the lower IRs of both PTC variants in the Black females than in non-Hispanic White females but higher AAPCs of incidence in the former than in the latter. Interestingly, the data also suggest that the rise in the IRs of PTC is becoming plateaued in the most recent 2 years. These novel observations are helpful in understanding the incidence and incidence trends of thyroid cancer.
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http://dx.doi.org/10.1530/ERC-15-0445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891202PMC
April 2016

The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met.

Oncotarget 2016 Mar;7(9):10472-85

Center for Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China.

The sonic hedgehog (Shh) pathway is highly activated in thyroid neoplasms and promotes thyroid cancer stem-like cell phenotype, but whether the Shh pathway regulates thyroid tumor cell motility and invasiveness remains unknown. Here, we report that the motility and invasiveness of two anaplastic thyroid tumor cell lines, KAT-18 and SW1736, were inhibited by two inhibitors of the Shh pathway (cyclopamine and GANT61). Consistently, the cell motility and invasiveness was decreased by Shh and Gli1 knockdown, and was increased by Gli1 overexpression in KAT-18 cells. Mechanistic studies revealed that Akt and c-Met phosphorylation was decreased by a Gli1 inhibitor and by Shh and Gli1 knockdown, but was increased by Gli1 overexpression. LY294002, a PI-3 kinase inhibitor, and a c-Met inhibitor inhibited the motility and invasiveness of Gli1-transfected KAT-18 cells more effectively than the vector-transfected cells. Knockdown of Snail, a transcription factor regulated by the Shh pathway, led to decreased cell motility and invasiveness in KAT-18 and SW1736 cells. However, key epithelial-to-mesenchymal transition (EMT) markers including E-cadherin and vimentin as well as Slug were not affected by cyclopamine and GANT61 in either SW1736 or WRO82, a well differentiated follicular thyroid carcinoma cell line. Our data suggest that the Shh pathway-stimulated thyroid tumor cell motility and invasiveness is largely mediated by AKT and c-Met activation with little involvement of EMT.
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http://dx.doi.org/10.18632/oncotarget.7228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891133PMC
March 2016