Endocrinology and Metabolism

Original Article

Thyroid
Distinct Impacts of Clinicopathological and Mutational Profiles on Long-Term Survival and Recurrence in Medullary Thyroid Carcinoma: Moon Young Oh, Kyong Yeun Jung, Hoonsung Choi, Young Jun Chai, Sun Wook Cho, Su-jin Kim, Kyu Eun Lee, Eun-Jae Chung, Do Joon Park, Young Joo Park, Han-Kwang Yang; Endocrinol Metab. 2024;39(6):877-890. Published online November 5, 2024; DOI: https://doi.org/10.3803/EnM.2024.2027

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Abstract PDF Supplementary Material PubReader ePub: Background
Medullary thyroid carcinoma (MTC) has a poorer prognosis than differentiated thyroid cancers; however, comprehensive data on the long-term outcomes of MTC remain scarce. This study investigated the extended clinical outcomes of MTC and aimed to identify prognostic factors.
Methods
Patients diagnosed with MTC between 1980 and 2020 were retrospectively reviewed. Their clinical characteristics, longterm clinical outcomes, and prognostic factors for recurrence and mortality were analyzed.
Results
The study included 226 patients (144 women, 82 men). The disease-specific survival (DSS) rates for all MTC patients at 5-, 10-, 20-, and 30-year intervals were 92.7%, 89.4%, 74.3%, and 68.1%, respectively. The recurrence-free survival (RFS) rates were 71.1%, 56.1%, 40.2%, and 32.1% at these intervals. DSS was comparable between the groups from 1980–2009 and 2010–2020 (P=0.995); however, the 1980–2009 group had significantly lower RFS rates (P=0.031). The 2010–2020 group exhibited greater extents of surgical and lymph node dissection (P=0.003) and smaller tumors (P=0.003). Multivariate analysis identified extrathyroidal extension as the strongest prognostic factor for both RFS and DSS. Age >55 years and tumor size of ≥2 cm were also significant prognostic factors for DSS, while hereditary disease and lymph node metastasis were significant for RFS. Survival analysis after propensity-score matching of rearranged during transfection (RET)-negative and non-screened RET-positive groups showed comparable DSS but longer RFS in the RET-negative group.
Conclusion
Extrathyroidal extension was identified as the strongest prognostic factor for RFS and DSS. Older age and larger tumor size were associated with decreased DSS, while RET mutation and lymph node metastasis significantly impacted RFS.

Brief Report

Adrenal Gland
A Novel Missense PRKAR1A Variant Causes Carney Complex: Boram Kim, Han Na Jang, Kyung Shil Chae, Ho Seop Shin, Yong Hwy Kim, Su Jin Kim, Moon-Woo Seong, Jung Hee Kim; Endocrinol Metab. 2022;37(5):810-815. Published online October 4, 2022; DOI: https://doi.org/10.3803/EnM.2022.1544

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The Carney complex (CNC) is an autosomal dominant disorder characterized by endocrine and nonendocrine tumors. Loss-of-function variants of protein kinase A regulatory subunit 1 alpha (PRKAR1A) are common causes of CNC. Here, we present the case of a patient with CNC with a novel PRKAR1A missense variant. A 21-year-old woman was diagnosed with CNC secondary to acromegaly and adrenal Cushing syndrome. Genetic analysis revealed a novel missense heterozygous variant of PRKAR1A (c.176A>T). Her relatives, suspected of having CNC, also carried the same variant. RNA analysis revealed that this variant led to nonsense-mediated mRNA decay. In vitro functional analysis of the variant confirmed its role in increasing protein kinase A activity and cyclic adenosine monophosphate levels. This study broadens our understanding of the genetic spectrum of CNC. We suggest that PRKAR1A genetic testing and counseling be recommended for patients with CNC and their families.

Citations

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Carney complex: A clinicopathologic study on a single family from several Canadian provinces
Alexandra Lao, Julio Silva, Brian Chiu, Consolato M. Sergi
Cardiovascular Pathology.2024; 69: 107599. CrossRef

Original Article

Thyroid
Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients: Heera Yang, Hyunju Park, Hyun Jin Ryu, Jung Heo, Jung-Sun Kim, Young Lyun Oh, Jun-Ho Choe, Jung Han Kim, Jee Soo Kim, Hye Won Jang, Tae Hyuk Kim, Sun Wook Kim, Jae Hoon Chung; Endocrinol Metab. 2022;37(4):652-663. Published online July 22, 2022; DOI: https://doi.org/10.3803/EnM.2022.1477

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Background
Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients.
Methods
We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma.
Results
Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences.
Conclusion
This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

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Giulia Orlando, Giulia Capella, Giulia Vocino Trucco, Elena Vissio, Jasna Metovic, Francesca Maletta, Marco Volante, Mauro Papotti
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Talal El Zarif, Marc Machaalani, Rashad Nawfal, Amin H Nassar, Wanling Xie, Toni K Choueiri, Mark Pomerantz
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Jiaqi Ji, Xinlong Shi
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2023 Update of the Korean Thyroid Association Guidelines for the Management of Thyroid Nodules
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L. Samuel Hellgren, Adam Stenman, Kenbugul Jatta, Vincenzo Condello, Catharina Larsson, Jan Zedenius, C. Christofer Juhlin
Endocrine Pathology.2024; 35(4): 411. CrossRef
Association Between Gross Features and Coexistence of BRAFV600E and TERT Promoter Mutations in Papillary Thyroid Carcinomas: A Combined Analysis Incorporating Clinicopathologic Features
Thi Ngoc Anh Nguyen, Van Phu Thang Nguyen, Hirokazu Kurohama, Yuko Akazawa, Katsuya Matsuda, Zhanna Mussazhanova, Yuki Matsuoka, Kenichi Yokota, Shinya Satoh, Hiroyuki Yamashita, Thi Nhung Nguyen, Yerkerzhan Sailaubekova, Masahiro Nakashima
Thyroid®.2024; 34(12): 1476. CrossRef
Are TERT Promoter Mutations a Poor Prognostic Factor in Anaplastic Thyroid Carcinoma?
Hyun Jin Ryu, Young Lyun Oh, Jung Heo, Hyunju Park, Tae Hyuk Kim, Sun Wook Kim, Jae Hoon Chung
International Journal of Thyroidology.2024; 17(2): 286. CrossRef
A Machine Learning-Based Model for Preoperative Assessment and Malignancy Prediction in Patients with Atypia of Undetermined Significance Thyroid Nodules
Gilseong Moon, Jae Hyun Park, Taesic Lee, Jong Ho Yoon
Journal of Clinical Medicine.2024; 13(24): 7769. CrossRef
Deciphering the Functions of Telomerase Reverse Transcriptase in Head and Neck Cancer
Tsung-Jang Yeh, Chi-Wen Luo, Jeng-Shiun Du, Chien-Tzu Huang, Min-Hung Wang, Tzer-Ming Chuang, Yuh-Ching Gau, Shih-Feng Cho, Yi-Chang Liu, Hui-Hua Hsiao, Li-Tzong Chen, Mei-Ren Pan, Hui-Ching Wang, Sin-Hua Moi
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2023 Korean Thyroid Association Management Guidelines for Patients with Thyroid Nodules
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International Journal of Thyroidology.2023; 16(1): 1. CrossRef
Thyroid Cancer, Iodine, and Gene Mutation
Jae Hoon Chung
International Journal of Thyroidology.2023; 16(1): 89. CrossRef
Mortality rate and causes of death in papillary thyroid microcarcinoma
Jung Heo, Hyun Jin Ryu, Hyunju Park, Tae Hyuk Kim, Sun Wook Kim, Young Lyun Oh, Jae Hoon Chung
Endocrine.2023; 83(3): 671. CrossRef
TERT promoter mutations in thyroid cancer
Michiko Matsuse, Norisato Mitsutake
Endocrine Journal.2023; 70(11): 1035. CrossRef
TERT Promoter and BRAF V600E Mutations in Papillary Thyroid Cancer: A Single-Institution Experience in Korea
Min Jhi Kim, Jin Kyong Kim, Gi Jeong Kim, Sang-Wook Kang, Jandee Lee, Jong Ju Jeong, Woong Youn Chung, Daham Kim, Kee-Hyun Nam
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Hyunju Park, Jae Hoon Chung
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Sue Youn Kim, Chan Kwon Jung
Endocrinology and Metabolism.2022; 37(6): 947. CrossRef

Review Article

Thyroid
Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer: Sang-Hyeon Ju, Seong Eun Lee, Yea Eun Kang, Minho Shong; Endocrinol Metab. 2022;37(1):53-61. Published online February 28, 2022; DOI: https://doi.org/10.3803/EnM.2022.1402

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Cancer therapies targeting genetic alterations are a topic of great interest in the field of thyroid cancer, which frequently harbors mutations in the RAS, RAF, and RET genes. Unfortunately, U.S. Food and Drug Administration-approved BRAF inhibitors have relatively low therapeutic efficacy against BRAF-mutant thyroid cancer; in addition, the cancer often acquires drug resistance, which prevents effective treatment. Recent advances in genomics and transcriptomics are leading to a more complete picture of the range of mutations, both driver and messenger, present in thyroid cancer. Furthermore, our understanding of cancer suggests that oncogenic mutations drive tumorigenesis and induce rewiring of cancer cell metabolism, which promotes survival of mutated cells. Synthetic lethality (SL) is a method of neutralizing mutated genes that were previously considered untargetable by traditional genotype-targeted treatments. Because these metabolic events are specific to cancer cells, we have the opportunity to develop new therapies that target tumor cells specifically without affecting healthy tissue. Here, we describe developments in metabolism-based cancer therapy, focusing on the concept of metabolic SL in thyroid cancer. Finally, we discuss the essential implications of metabolic reprogramming and its role in the future direction of SL for thyroid cancer.

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Emerging Strategies for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Combining Immune Checkpoint Inhibitors with VEGF Inhibitors
Young Joo Park
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Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer
Aliya Lakhani, Da Hyun Kang, Yea Eun Kang, Junyoung O. Park
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The Role of De novo Serine Biosynthesis from Glucose in Papillary Thyroid Cancer
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Original Articles

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.

Thyroid
Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis: Mijin Kim, Chae Hwa Kwon, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yun Kyung Jeon, Sang Soo Kim, Kyung-Un Choi, In Joo Kim, Meeyoung Park, Bo Hyun Kim; Endocrinol Metab. 2021;36(5):1086-1094. Published online October 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1132

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Background
Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC.
Methods
Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues.
Results
The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher’s exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs.
Conclusion
This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.

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What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?
Bobby White, Pawel Swietach
Pflügers Archiv - European Journal of Physiology.2024; 476(4): 673. CrossRef
Comprehensive Long-Read Sequencing Analysis Discloses the Transcriptome Features of Papillary Thyroid Microcarcinoma
Yanqiang Wang, Binbin Zou, Yanyan Zhang, Jin Zhang, Shujing Li, Bo Yu, Zhekun An, Lei Li, Siqian Cui, Yutong Zhang, Jiali Yao, Xiuzhi Shi, Jing Liu
The Journal of Clinical Endocrinology & Metabolism.2024; 109(5): 1263. CrossRef
Feasibility of whole‐exome sequencing in fine‐needle aspiration specimens of papillary thyroid microcarcinoma for the identification of novel gene mutations
Liyuan Ma, Luying Gao, Ya Hu, Xiaoyi Li, Chunhao Liu, Jiang Ji, Xinlong Shi, Aonan Pan, Yuang An, Nengwen Luo, Yu Xia, Yuxin Jiang
Clinical Genetics.2024; 105(5): 567. CrossRef
Multi-omics analysis reveals a molecular landscape of the early recurrence and early metastasis in pan-cancer
Dan-ni He, Na Wang, Xiao-Ling Wen, Xu-Hua Li, Yu Guo, Shu-heng Fu, Fei-fan Xiong, Zhe-yu Wu, Xu Zhu, Xiao-ling Gao, Zhen-zhen Wang, Hong-jiu Wang
Frontiers in Genetics.2023;[Epub] CrossRef

Clinical Study
Molecular Correlates and Nuclear Features of Encapsulated Follicular-Patterned Thyroid Neoplasms: Chan Kwon Jung, Andrey Bychkov, Dong Eun Song, Jang-Hee Kim, Yun Zhu, Zhiyan Liu, Somboon Keelawat, Chiung-Ru Lai, Mitsuyoshi Hirokawa, Kaori Kameyama, Kennichi Kakudo; Endocrinol Metab. 2021;36(1):123-133. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.860

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Background
Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAFV^600E mutation.
Methods
Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing.
Results
Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAFV^600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAFV^600E than for those with RAS-like mutations (P<0.001).
Conclusion
Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAFV^600E mutation from benign or borderline follicular tumors with RAS-like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAFV^600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.

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Prognosis of invasive encapsulated follicular variant and classical papillary thyroid carcinoma: a propensity score-matched study using the SEER database
Shuai Jin, Lang Xie, Gongyou Zhang, Lei Liu, Kaide Xia, Hongzhou Liu, Haiwang Zhang, Peng Li
Scientific Reports.2025;[Epub] CrossRef
Nuclear pseudoinclusion is associated with BRAFV600E mutation: Analysis of nuclear features in papillary thyroid carcinoma
Agnes Stephanie Harahap, Dina Khoirunnisa, Salinah, Maria Francisca Ham
Annals of Diagnostic Pathology.2025; 75: 152434. CrossRef
Differentiating BRAF V600E- and RAS-like alterations in encapsulated follicular patterned tumors through histologic features: a validation study
Chankyung Kim, Shipra Agarwal, Andrey Bychkov, Jen-Fan Hang, Agnes Stephanie Harahap, Mitsuyoshi Hirokawa, Kennichi Kakudo, Somboon Keelawat, Chih-Yi Liu, Zhiyan Liu, Truong Phan-Xuan Nguyen, Chanchal Rana, Huy Gia Vuong, Yun Zhu, Chan Kwon Jung
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Moon Young Oh, Hye-Mi Choi, Jinsun Jang, Heejun Son, Seung Shin Park, Minchul Song, Yoo Hyung Kim, Sun Wook Cho, Young Jun Chai, Woosung Chung, Young Joo Park
Endocrinology and Metabolism.2024; 39(5): 777. CrossRef
Diagnostic challenges in the assessment of thyroid neoplasms using nuclear features and vascular and capsular invasion: a multi-center interobserver agreement study
Agnes Stephanie Harahap, Mutiah Mutmainnah, Maria Francisca Ham, Dina Khoirunnisa, Abdillah Hasbi Assadyk, Husni Cangara, Aswiyanti Asri, Diah Prabawati Retnani, Fairuz Quzwain, Hasrayati Agustina, Hermawan Istiadi, Indri Windarti, Krisna Murti, Muhammad
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The Presence of Typical “BRAFV600E-Like” Atypia in Papillary Thyroid Carcinoma is Highly Specific for the Presence of the BRAFV600E Mutation
John Turchini, Loretta Sioson, Adele Clarkson, Amy Sheen, Leigh Delbridge, Anthony Glover, Mark Sywak, Stan Sidhu, Anthony J. Gill
Endocrine Pathology.2023; 34(1): 112. CrossRef
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Maria Kościuszko, Angelika Buczyńska, Adam Jacek Krętowski, Anna Popławska-Kita
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Pitfalls in thyroid pathology and the medicolegal aspects of error
David N Poller
Diagnostic Histopathology.2023; 29(11): 495. CrossRef
Developing Models to Predict BRAFV600E and RAS Mutational Status in Papillary Thyroid Carcinoma Using Clinicopathological Features and pERK1/2 Immunohistochemistry Expression
Agnes Stephanie Harahap, Imam Subekti, Sonar Soni Panigoro, Asmarinah, Lisnawati, Retno Asti Werdhani, Hasrayati Agustina, Dina Khoirunnisa, Mutiah Mutmainnah, Fajar Lamhot Gultom, Abdillah Hasbi Assadyk, Maria Francisca Ham
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Kennichi Kakudo, Chan Kwon Jung, Zhiyan Liu, Mitsuyoshi Hirokawa, Andrey Bychkov, Huy Gia Vuong, Somboon Keelawat, Radhika Srinivasan, Jen-Fan Hang, Chiung-Ru Lai
Journal of Pathology and Translational Medicine.2023; 57(6): 289. CrossRef
Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Tumour Entity with a Short History. A Review on Challenges in Our Microscopes, Molecular and Ultrasonographic Profile
Ivana Kholová, Elina Haaga, Jaroslav Ludvik, David Kalfert, Marie Ludvikova
Diagnostics.2022; 12(2): 250. CrossRef
Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach
Chan Kwon Jung, Andrey Bychkov, Kennichi Kakudo
Endocrinology and Metabolism.2022; 37(5): 703. CrossRef
Different Threshold of Malignancy for RAS-like Thyroid Tumors Causes Significant Differences in Thyroid Nodule Practice
Kennichi Kakudo
Cancers.2022; 14(3): 812. CrossRef
The Incidence of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: A Meta-Analysis Assessing Worldwide Impact of the Reclassification
Chanchal Rana, Huy Gia Vuong, Thu Quynh Nguyen, Hoang Cong Nguyen, Chan Kwon Jung, Kennichi Kakudo, Andrey Bychkov
Thyroid.2021;[Epub] CrossRef

Clinical Study
Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma: Soo Hyun Seo, Jung Hee Kim, Man Jin Kim, Sung Im Cho, Su Jin Kim, Hyein Kang, Chan Soo Shin, Sung Sup Park, Kyu Eun Lee, Moon-Woo Seong; Endocrinol Metab. 2020;35(4):909-917. Published online December 23, 2020; DOI: https://doi.org/10.3803/EnM.2020.756

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Background
Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.
Methods
Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.
Results
Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.
Conclusion
Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.

Citations

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Patient Sex and Origin Influence Distribution of Driver Genes and Clinical Presentation of Paraganglioma
Susan Richter, Nicole Bechmann
Journal of the Endocrine Society.2024;[Epub] CrossRef
Germline Mutations and Phenotypic Associations in Korean Patients With Pheochromocytoma and Paraganglioma: A Multicenter Study and Literature Review
Kwan Hoon Jo, Jaewoong Lee, Jaeeun Yoo, Hoon Seok Kim, Eun Sook Kim, Je Ho Han, Yi Sun Jang, Jae-Seung Yun, Jang Won Son, Soon Jib Yoo, Seung Hwan Lee, Dong Jun Lim, Hyuk-Sang Kwon, Seungok Lee, Sungdae Moon, Myungshin Kim
Annals of Laboratory Medicine.2024; 44(6): 591. CrossRef
Clinical exome next‑generation sequencing panel for hereditary pheochromocytoma and paraganglioma diagnosis
Beatrice Melli, Vincenza Cusenza, Sandra Martinelli, Federica Castiglione, Loretta Fornaciari, Andrea Palicelli, Luca Braglia, Enrico Farnetti, Aurelio Negro, Simonetta Rosato, Andrea Frasoldati, Maicol Baldini, Chiara Grasselli, Davide Nicoli
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Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force
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Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas
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International Journal of Endocrinology.2021; 2021: 1. CrossRef

Clinical Study
Genetic Analysis and Clinical Characteristics of Hereditary Pheochromocytoma and Paraganglioma Syndrome in Korean Population: Heewon Choi, Kyoung Jin Kim, Namki Hong, Saeam Shin, Jong-Rak Choi, Sang Wook Kang, Seung Tae Lee, Yumie Rhee; Endocrinol Metab. 2020;35(4):858-872. Published online December 23, 2020; DOI: https://doi.org/10.3803/EnM.2020.683

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Background
Pheochromocytoma and paragangliomas (PPGL) are hereditary in approximately 30% to 40% cases. With the advancement of genetic analysis techniques, including next-generation sequencing (NGS), there were attempts to classify PPGL into molecular clusters. With NGS being applied to clinical settings recently, we aimed to review the results of genetic analysis, including NGS, and investigate the association with clinical characteristics in Korean PPGL patients.
Methods
We reviewed the medical records of PPGL patients who visited Severance hospital from 2006 to 2019. We documented the clinical phenotype of those who underwent targeted NGS or had known germline mutations of related genes.
Results
Among 57 PPGL patients, we found 28 pathogenic germline mutations of susceptibility genes. Before the targeted NGS was implemented, only obvious syndromic feature lead to the Sanger sequencing for the specific genes. Therefore, for the exact prevalence, only patients after the year 2017, when targeted NGS was added, were included (n=43). The positive germline mutations were found in 14 patients; thus, the incidence rate is 32.6%. Patients with germline mutations had a higher likelihood of family history. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate, presence of other tumors, and biochemical profile among three molecular clusters: pseudohypoxic tricarboxylic acid cycle-related, pseudohypoxic von Hippel-Lindau (VHL)/endothelial PAS domain-containing protein 1-related, and kinase-signaling group. Germline mutations were identified in seven PPGL-related genes (SDHB, RET, VHL, NF1, MAX, SDHA, and SDHD).
Conclusion
We report the expected prevalence of germline mutations in Korean PPGL patients. NGS is a useful and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification is needed for precise management.

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Review Articles

Thyroid
Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification: Yanhua Bai, Kennichi Kakudo, Chan Kwon Jung; Endocrinol Metab. 2020;35(4):696-715. Published online December 2, 2020; DOI: https://doi.org/10.3803/EnM.2020.807

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Abstract PDF PubReader ePub

Advances in medical sciences and evidence-based medicine have led to momentous changes in classification and management of thyroid neoplasms. Much progress has been made toward avoiding overdiagnosis and overtreatment of thyroid cancers. The new 2017 World Health Organization (WHO) classification of thyroid neoplasms updated the diagnostic criteria and molecular and genetic characteristics reflecting the biology and behavior of the tumors, and newly introduced the category of borderline malignancy or uncertain malignant potential. Some neoplasms were subclassified, renamed, or redefined as a specific entity. This review introduces changes in the fourth edition WHO classification of thyroid tumors and updates the contemporary diagnosis and classification of thyroid tumors. We also discuss several challenges with the proposal of new diagnostic entities, since they have unique histopathologic and molecular features and clinical relevance.

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Miscellaneous
Rare PTH Gene Mutations Causing Parathyroid Disorders: A Review: Joon-Hyop Lee, Munkhtugs Davaatseren, Sihoon Lee; Endocrinol Metab. 2020;35(1):64-70. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.64

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Since parathyroid hormone (PTH) was first isolated and its gene (PTH) was sequenced, only eight PTH mutations have been discovered. The C18R mutation in PTH, discovered in 1990, was the first to be reported. This autosomal dominant mutation induces endoplasmic reticulum stress and subsequent apoptosis in parathyroid cells. The next mutation, which was reported in 1992, is associated with exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the second exon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at the same residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somatic R83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, a heterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation was reported; this is the only reported hypoparathyroidism-causing mutation in the mature bioactive part of PTH. In 2017, another heterozygous mutation, M14K, was detected. The discovery of these eight mutations in the PTH gene has provided insights into its function and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detect other such mutations will help elucidate the functions of PTH in a more sophisticated manner.

Citations

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The Molecular Biology of Placental Transport of Calcium to the Human Foetus
Valerie Walker
International Journal of Molecular Sciences.2025; 26(1): 383. CrossRef
Hypoparathyroidism: Similarities and differences between Western and Eastern countries
Yu-ying Yang, Yan-hua Deng, Li-hao Sun, Lars Rejnmark, Ling Wang, Peter Pietschmann, Claus‐Christian Glüer, Aliya A. Khan, Salvatore Minisola, Jian-min Liu
Osteoporosis International.2025; 36(3): 391. CrossRef
The Intricacies of Renal Phosphate Reabsorption—An Overview
Valerie Walker
International Journal of Molecular Sciences.2024; 25(9): 4684. CrossRef
Case report: Familial hypoparathyroidism with elevated parathyroid hormone due to an inactivating PTH mutation
Noha Mukhtar, Balgees Alghamdi, Meshael Alswailem, Afaf Alsagheir, Ali S. Alzahrani
Frontiers in Endocrinology.2024;[Epub] CrossRef
Primary Hyperparathyroidism With Undetectable Intact Parathyroid Hormone
Zhixing Song, Jessica McMullin, Forest Huls, Richard Rosenthal, Sravani Bantu, Christopher Wu, Herbert Chen, Brenessa Lindeman
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Enhancing bone regeneration and osseointegration using rhPTH(1-34) and dimeric R25CPTH(1-34) in an osteoporotic beagle model
Jeong-Oh Shin, Jong-Bin Lee, Sihoon Lee, Jin-Woo Kim
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Molecular and Clinical Spectrum of Primary Hyperparathyroidism
Smita Jha, William F Simonds
Endocrine Reviews.2023; 44(5): 779. CrossRef
Rare cause of persistent hypocalcaemia in infancy due to PTH gene mutation
Savita Khadse, Vrushali Satish Takalikar, Radha Ghildiyal, Nikhil Shah
BMJ Case Reports.2023; 16(9): e256358. CrossRef
Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone
Patrick Hanna, Ashok Khatri, Shawn Choi, Severine Brabant, Matti L. Gild, Marie L. Piketty, Bruno Francou, Dominique Prié, John T. Potts, Roderick J. Clifton-Bligh, Agnès Linglart, Thomas J. Gardella, Harald Jüppner
Proceedings of the National Academy of Sciences.2023;[Epub] CrossRef
Genetics of monogenic disorders of calcium and bone metabolism
Paul J. Newey, Fadil M. Hannan, Abbie Wilson, Rajesh V. Thakker
Clinical Endocrinology.2022; 97(4): 483. CrossRef
Homozygous missense variant of PTH (c.166C>T, p.(Arg56Cys)) as the cause of familial isolated hypoparathyroidism in a three-year-old child
Stine Linding Andersen, Anja Lisbeth Frederiksen, Astrid Bruun Rasmussen, Mette Madsen, Ann-Margrethe Rønholt Christensen
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Novel PTH Gene Mutations Causing Isolated Hypoparathyroidism
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Original Articles

A Study of Point Mutations of Human Insulin-like Growth Factor - 1 (IGF - 1) Promoter Gene in Familial Short Stature (FSS) Patients.: In Myung Yang, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Young Kil Choi, Hyun Ha Chang, In Kyung Jung, Tae Kwan Park; J Korean Endocr Soc. 1996;11(4):500-509. Published online November 7, 2019

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Abstract PDF: Background
FSS is a normal variants in Korea, but some of them had defect of noctumal GH pulse i.e. neurosecretory dysfunction. Although Korean children had strikingly got higher final height in the last decade. We are interested in what kinds of differences were existed in FSS group. Previous study showed theres no difference of GH related biochemical markers between normal and FSS group, like IGF-I, IGFBP-3 etc. We analyzed molecular difference in FSS group. Methods: We screened 23 FSS patients and 16 normal controls to IGF-I gene prornoter region with PCR-SSCP (single strand conformation polymorphisrn) method and sequenced 1 FSS patients who had abnormal SSCP band. Results: We found 1 out of 23 patients with abnormal SSCP band (none for 16 controls). Their IGF-I promoter gene were sequenced with modified Maxam-Gilbert method. One subject had 2 point mutations(+8 and +74). Conclusion: We found point mutations of IGF-I promoter in FSS group, This position was regarded as HNF(hepatic nuclear factor)-3 binding sites. We needed more study for the detection of its biological function according io linear growth with in vivo and in vitro study.

Molecular Genetic Studies on the Human CYP21A2 Gene (1).: Byung Kiu Park, Hyang Ok Woo, Han Wook Woo; J Korean Endocr Soc. 1994;9(3):219-227. Published online November 6, 2019

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Abstract PDF: Congenital adrenal hyperplasia, especially due to steroid-12-hydroxylase(P450c21) deficiency, is one of the most common autosomal recessive inborn errors at adrenal steroidogenesis in Korean. Molecular genetic analysis has demonstrated that there are two steroid 21-hydroxylase genes, CYP21A1P and CYP21A2. The CYP21A2 gene encodes P450c21, whereas the CYP21A1P gene is a pseudogene. Since there is 98 percent homology between the CYP21A1P and CYP21A2 gene in nucleotide sequences, it has hampered the characterization of molecular defects in the CYP21A2 gene.In this study, efforts have been made to selectively PCR amplify the CYP21A2 gene and test feasibility of DNA microextraction from Guthrie card for prospective use of molecular screening. This study was also aimed at investigating deletion mutations in P450c21 deficient patients, as well as allele frequencies and average heterozygosity of exon 1 A/C polymorphism in Korean newborns. Genomic DNAs were obtained from Guthrie cards of 50 Korean newborns by microextraction method and these DNAs were analyzed by PCR-allele specific oligonucleotide(ASO) hybridization. First part of the CYP21A2 gene has been successfully amplified and digested by restriction enzyme using Taq I or Kpn I, subsequently run on 1.5% agarose gel to confirm its specificity. The anterior 1141 bp PCR product was utilized to examine the frequency and average heterozygosity of exon 1 A/C polymorphism in 100 alleles by ASO dot blot hybridization. Amplified genomic DNAs from four P450c21 deficient patients out of three families were screened by PCR to see if any one has complete deletion of the CYP21A2 gene.The results were as follows;1) The average 1230ng of genomic DNA was obtained form single semi-circled Guthrie card of 1/2 inch diameter by microextraction method, which has been successfully used for DNA analysis.2) The PCR amplified anterior 1141 bp product from the CYP21A2 gene was digested by Kpn I, generating 309 bp, 832 bp fragments, not by Taq I, indicating its specificity.3) The frequencies of exon 1 nucleotide 138 A/C polymorphism in Korean population were 0.81, 0.91 respectively, and average heterozygosity was 0.31.4) None of four P450c21 deficient patients turned out to carry complete deletion of the CYP21A2 gene based on selective PCR amplification of the CYP21A2 gene.In conclusion, dried blood spots from Guthrie card can be sued for DNA analysis because of easy sample collection, bandling, shipment, and DNA extraction feasibility. The selective PCR amplification of the CYP 21A2 gene will pave the way for molecular characterization in P450c21 deficient patients. The exon 1 A/C polymorphism can by efficiently used for molecular diagnosis of P450c21 deficiency in informative families, though it has a drawback of handling radioactive material.

Endocrine Research
Expression of NF2 Modulates the Progression of BRAF^V600E Mutated Thyroid Cancer Cells: Mi-Hyeon You, Min Ji Jeon, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Won Gu Kim; Endocrinol Metab. 2019;34(2):203-212. Published online June 24, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.2.203

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Background

We previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAF^V600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation.

Methods

To identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAF^V600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data.

Results

First, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288^* and Q470^* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis.

Conclusion

Our study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.

Citations

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Mechanistic Insights of Thyroid Cancer Progression
Luis Javier Leandro-García, Iñigo Landa
Endocrinology.2023;[Epub] CrossRef
Gene Editing with CRISPR/Cas Methodology and Thyroid Cancer: Where Are We?
Cesar Seigi Fuziwara, Diego Claro de Mello, Edna Teruko Kimura
Cancers.2022; 14(3): 844. CrossRef
Extracellular Vesicles as Signal Carriers in Malignant Thyroid Tumors?
Małgorzata Grzanka, Anna Stachurska-Skrodzka, Anna Adamiok-Ostrowska, Ewa Gajda, Barbara Czarnocka
International Journal of Molecular Sciences.2022; 23(6): 3262. CrossRef
Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression
Mi-Hyeon You, Min Ji Jeon, Seong ryeong Kim, Woo Kyung Lee, Sheue-yann Cheng, Goo Jang, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Won Gu Kim
Scientific Reports.2021;[Epub] CrossRef
High Phosphoglycerate Dehydrogenase Expression Induces Stemness and Aggressiveness in Thyroid Cancer
Min Ji Jeon, Mi-Hyeon You, Ji Min Han, Soyoung Sim, Hyun Ju Yoo, Woo Kyung Lee, Tae Yong Kim, Dong Eun Song, Young Kee Shong, Won Gu Kim, Won Bae Kim
Thyroid.2020; 30(11): 1625. CrossRef

Review Article

Miscellaneous
Search for Novel Mutational Targets in Human Endocrine Diseases: So Young Park, Myeong Han Seo, Sihoon Lee; Endocrinol Metab. 2019;34(1):23-28. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.23

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The identification of disease-causing genetic variations is an important goal in the field of genetics. Advancements in genetic technology have changed scientific knowledge and made it possible to determine the basic mechanism and pathogenesis of human disorders rapidly. Many endocrine disorders are caused by genetic variations of a single gene or by mixed genetic factors. Various genetic testing methods are currently available, enabling a more precise diagnosis of many endocrine disorders and facilitating the development of a concrete therapeutic plan. In this review article, we discuss genetic testing technologies for genetic endocrine disorders, with relevant examples. We additionally describe our research on implementing genetic analysis strategies to identify novel causal mutations in hypocalcemia-related disorders.

Citations

Citations to this article as recorded by

EndoGene database: reported genetic variants for 5,926 Russian patients diagnosed with endocrine disorders
Anton A. Buzdin, Marianna A. Zolotovskaia, Sergey A. Roumiantsev, Aleksandra G. Emelyanova, Olga O. Golounina, Polina A. Pugacheva, Daniil V. Luppov, Anastasia V. Kuzminyh, Arseniya O. Alexeeva, Anna A. Emelianova, Alexey L. Novoselov, Alina Matrosova, An
Frontiers in Endocrinology.2025;[Epub] CrossRef

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