Endocrinology and Metabolism

Original Articles

Thyroid
BRAF^V600E Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors: Minjun Kim, Su-jin Kim, Seong Yun Ha, Zhen Xu, Youngjin Han, Hyeon-Gun Jee, Sun Wook Cho, Young Joo Park, Kyu Eun Lee; Endocrinol Metab. 2022;37(6):879-890. Published online December 26, 2022; DOI: https://doi.org/10.3803/EnM.2022.1563

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Background
Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of BRAF^V600E in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of BRAF^V600E on the estrogen-induced increase in metastatic potential in thyroid cancer.
Methods
Using a pair of cell lines, human thyroid cell lines which harbor wild type BRAF gene (Nthy/WT) and Nthy/BRAF^V600E (Nthy/V600E), the expression of estrogen receptors (ERs) and estrogen-induced metastatic phenotypes were evaluated. Susceptibility to ERα- and ERβ-selective agents was evaluated to confirm differential ER expression. ESR expression was analyzed according to BRAF^V600E status and age (≤50 years vs. >50 years) using The Cancer Genome Atlas (TCGA) data.
Results
Estradiol increased the ERα/ERβ expression ratio in Nthy/V600E, whereas the decreased ERα/ERβ expression ratio was found in Nthy/WT. BRAF^V600E-mutated cell lines showed a higher E2-induced increase in metastatic potential, including migration, invasion, and anchorage-independent growth compared with Nthy/WT. An ERα antagonist significantly inhibited migration in Nthy/V600E cells, whereas an ERβ agonist was more effective in Nthy/WT. In the BRAF^V600E group, ESR1/ESR2 ratio was significantly higher in younger age group (≤50 years) compared with older age group (>50 years) by TCGA data analysis.
Conclusion
Our data show that BRAF^V600E mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, BRAF^V600E might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.

Citations

Citations to this article as recorded by

The importance of protein domain mutations in cancer therapy
Kiran Kumar Chitluri, Isaac Arnold Emerson
Heliyon.2024; 10(6): e27655. CrossRef
Three cases of thyroid cancer in transgender female veterans receiving gender-affirming estrogen treatment
John D. Christensen, Hiba T. Basheer
Endocrine and Metabolic Science.2024; 15: 100177. CrossRef
Thyroid Cancer Prevalence, Risk Exposure, and Clinical Features Among Transgender Female Veterans
John David Christensen, Hiba T Basheer, Jose Joaquin Lado Abeal
Journal of the Endocrine Society.2024;[Epub] CrossRef
Association of DNA Promoter Methylation and BRAF Mutation in Thyroid Cancer
Farzana Jasmine, Briseis Aschebrook-Kilfoy, Mohammad M. Rahman, Garrett Zaagman, Raymon H. Grogan, Mohammed Kamal, Habibul Ahsan, Muhammad G. Kibriya
Current Oncology.2023; 30(3): 2978. CrossRef
Editorial: Recent advances in papillary thyroid carcinoma: Progression, treatment and survival predictors
Erivelto Martinho Volpi, Margarita Carmen Ramirez-Ortega, Jose Federico Carrillo
Frontiers in Endocrinology.2023;[Epub] CrossRef

Adrenal Gland
Clinical and Molecular Characteristics of PRKACA L206R Mutant Cortisol-Producing Adenomas in Korean Patients: Insoon Jang, Su-jin Kim, Ra-Young Song, Kwangsoo Kim, Seongmin Choi, Jang-Seok Lee, Min-Kyeong Gwon, Moon Woo Seong, Kyu Eun Lee, Jung Hee Kim; Endocrinol Metab. 2021;36(6):1287-1297. Published online December 2, 2021; DOI: https://doi.org/10.3803/EnM.2021.1217

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Abstract PDF Supplementary Material PubReader ePub: Background
An activating mutation (c.617A>C/p.Lys206Arg, L206R) in protein kinase cAMP-activated catalytic subunit alpha (PRKACA) has been reported in 35% to 65% of cases of cortisol-producing adenomas (CPAs). We aimed to compare the clinical characteristics and transcriptome analysis between PRKACA L206R mutants and wild-type CPAs in Korea.
Methods
We included 57 subjects with CPAs who underwent adrenalectomy at Seoul National University Hospital. Sanger sequencing for PRKACA was conducted in 57 CPA tumor tissues. RNA sequencing was performed in 13 fresh-frozen tumor tissues.
Results
The prevalence of the PRKACA L206R mutation was 51% (29/57). The mean age of the study subjects was 42±12 years, and 87.7% (50/57) of the patients were female. Subjects with PRKACA L206R mutant CPAs showed smaller adenoma size (3.3±0.7 cm vs. 3.8±1.2 cm, P=0.059) and lower dehydroepiandrosterone sulfate levels (218±180 ng/mL vs. 1,511±3,307 ng/mL, P=0.001) than those with PRKACA wild-type CPAs. Transcriptome profiling identified 244 differentially expressed genes (DEGs) between PRKACA L206R mutant (n=8) and wild-type CPAs (n=5), including five upregulated and 239 downregulated genes in PRKACA L206R mutant CPAs (|fold change| ≥2, P<0.05). Among the upstream regulators of DEGs, CTNNB1 was the most significant transcription regulator. In several pathway analyses, the Wnt signaling pathway was downregulated and the steroid biosynthesis pathway was upregulated in PRKACA mutants. Protein-protein interaction analysis also showed that PRKACA downregulates Wnt signaling and upregulates steroid biosynthesis.
Conclusion
The PRKACA L206R mutation in CPAs causes high hormonal activity with a limited proliferative capacity, as supported by transcriptome profiling.

Clinical Study
Efficacy of Intraoperative Neuromonitoring in Reoperation for Recurrent Thyroid Cancer Patients: Jang-il Kim, Su-jin Kim, Zhen Xu, JungHak Kwak, Jong-hyuk Ahn, Hyeong Won Yu, Young Jun Chai, June Young Choi, Kyu Eun Lee; Endocrinol Metab. 2020;35(4):918-924. Published online December 23, 2020; DOI: https://doi.org/10.3803/EnM.2020.778

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Background
The use of intraoperative neuromonitoring (IONM) in thyroid surgery to preserve recurrent laryngeal nerve (RLN) function has been widely accepted. We aimed to evaluate the usefulness of IONM in reoperation for recurrent thyroid cancer patients to help identify the RLN and prevent vocal cord palsy (VCP).
Methods
We analyzed 121 consecutive patients (with IONM group, 48 patients; without IONM group, 73 patients) who underwent reoperation for recurrent thyroid cancer after total thyroidectomy from January 2009 to March 2019 in our institution without VCP due to previous operations. Data including age, sex, number of previous operations, histologic subtype of the malignancy at the initial operation, operation time, RLNs at risk, difficulty of RLN identification, surgical procedure, VCP, and other postoperative complications were reviewed. Vocal cord movement evaluations were performed preoperatively and at 2 weeks postoperatively to evaluate RLN function. In patients with VCP, additional evaluations were performed. VCP exceeding 12 months after surgery was considered permanent VCP.
Results
VCP was observed in six (12.5%) and 16 (21.9%) patients with and without IONM (P=0.189). Transient and permanent VCP were found in three (6.3%) and three (6.3%) patients with IONM (P=0.098 and P=0.982, respectively) versus in 12 (16.4%) and four (5.5%) patients without IONM.
Conclusion
The incidence of transient VCP seems to be lower in reoperations with IONM; however, there was no statistical significances. Further study will be needed to ascertain the efficacy of IONM in reoperation for recurrent thyroid cancer patients.

Citations

Citations to this article as recorded by

The learning curve for gasless transaxillary posterior endoscopic thyroidectomy for thyroid cancer: a cumulative sum analysis
Weisheng Chen, Shitong Yu, Baihui Sun, Cangui Wu, Tingting Li, Shumin Dong, Junna Ge, Shangtong Lei
Updates in Surgery.2023; 75(4): 987. CrossRef
Intraoperative neuromonitoring of the recurrent laryngeal nerve is indispensable during complete endoscopic radical resection of thyroid cancer: A retrospective study
Yang Fei, Yang Li, Feng Chen, Wen Tian
Laryngoscope Investigative Otolaryngology.2022; 7(4): 1217. CrossRef
The value of intraoperative nerve monitoring against recurrent laryngeal nerve injury in thyroid reoperations
Maowei Pei, Siqi Zhu, Chunjie Zhang, Guoliang Wang, Mingrong Hu
Medicine.2021; 100(51): e28233. CrossRef

Corrigendum

Miscellaneous
Corrigendum: Author's Name Correction. Study Protocol of Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro): Jae Hoon Moon, Ji-hoon Kim, Eun Kyung Lee, Kyu Eun Lee, Sung Hye Kong, Yeo Koon Kim, Woo-Jin Jeong, Chang Yoon Lee, Roh-Eul Yoo, Yul Hwangbo, Young Shin Song, Min Joo Kim, Sun Wook Cho, Su-jin Kim, Eun-Jae Chung, June Young Choi, Chang Hwan Ryu, You Jin Lee, Jeong Hun Hah, Yuh-Seog Jung, Junsun Ryu, Yunji Hwang, Sue K. Park, Ho Kyung Sung, Ka Hee Yi, Do Joon Park, Young Joo Park; Endocrinol Metab. 2018;33(3):427. Published online August 14, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.3.427

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Citations

Citations to this article as recorded by

Invasiveness and Metastatic Aggressiveness in Small Differentiated Thyroid Cancers: Demography of Small Papillary Thyroid Carcinomas in the Swedish Population
Haytham Bayadsi, Martin Bergman, Malin Sund, Joakim Hennings
World Journal of Surgery.2020; 44(2): 461. CrossRef
Clinical and pathologic predictors of lymph node metastasis in papillary thyroid microcarcinomas
Ling Zhao, Xiaoya Sun, Yukun Luo, Fulin Wang, Zhaohui Lyu
Annals of Diagnostic Pathology.2020; 49: 151647. CrossRef

Original Article

Thyroid
Study Protocol of Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro): Jae Hoon Moon, Ji-hoon Kim, Eun Kyung Lee, Kyu Eun Lee, Sung Hye Kong, Yeo Koon Kim, Woo-jin Jung, Chang Yoon Lee, Roh-Eul Yoo, Yul Hwangbo, Young Shin Song, Min Joo Kim, Sun Wook Cho, Su-jin Kim, Eun Jae Jung, June Young Choi, Chang Hwan Ryu, You Jin Lee, Jeong Hun Hah, Yuh-Seog Jung, Junsun Ryu, Yunji Hwang, Sue K. Park, Ho Kyung Sung, Ka Hee Yi, Do Joon Park, Young Joo Park; Endocrinol Metab. 2018;33(2):278-286. Published online June 21, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.2.278

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Background

The ongoing Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) aims to observe the natural course of papillary thyroid microcarcinoma (PTMC), develop a protocol for active surveillance (AS), and compare the long-term prognosis, quality of life, and medical costs between the AS and immediate surgery groups.

Methods

This multicenter prospective cohort study of PTMC started in June 2016. The inclusion criteria were suspicious of malignancy or malignancy based on fine needle aspiration or core needle biopsy, age of ≥18 years, and a maximum diameter of ≤1 cm. If there was no major organ involvement, no lymph node/distant metastasis, and no variants with poor prognosis, the patients were explained of the pros and cons of immediate surgery and AS before selecting AS or immediate surgery. Follow-up visits (physical examination, ultrasonography, thyroid function, and questionnaires) are scheduled every 6 months during the first 2 years, and then every 1 year thereafter. Progression was defined as a maximum diameter increase of ≥3, ≥2 mm in two dimensions, suspected organ involvement, or lymph node/distant metastasis.

Results

Among 439 enrolled patients, 290 patients (66.1%) chose AS and 149 patients (33.9%) chose immediate surgery. The median follow-up was 6.7 months (range, 0.2 to 11.9). The immediate surgery group had a larger maximum tumor diameter, compared to the AS group (7.1±1.9 mm vs. 6.6±2.0 mm, respectively; P=0.014).

Conclusion

The results will be useful for developing an appropriate PTMC treatment policy based on its natural course and risk factors for progression.

Citations

Citations to this article as recorded by

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