Endocrinology and Metabolism

Original Article

Clinical Study
Lactate Dehydrogenase A as a Potential New Biomarker for Thyroid Cancer: Eun Jeong Ban, Daham Kim, Jin Kyong Kim, Sang-Wook Kang, Jandee Lee, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung, Kunhong Kim; Endocrinol Metab. 2021;36(1):96-105. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.819

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Background
Several cancers show increased levels of lactate dehydrogenase A (LDHA), which are associated with cancer progression. However, it remains unclear whether LDHA levels are associated with papillary thyroid cancer (PTC) aggressiveness or with the presence of the PTC prognostic marker, the BRAFV^600E mutation. This study aimed to evaluate the potential of LDHA as a PTC prognostic marker.
Methods
LDHA expression was examined in 83 PTC tissue specimens by immunohistochemistry. Human thyroid cell lines were genetically manipulated to overexpress BRAFV^600E or were treated with a BRAF-specific short hairpin RNA (shBRAF), whose effects on LDHA expression were evaluated by Western blotting. Data from 465 PTC patients were obtained from The Cancer Genome Atlas (TCGA) database and analyzed to validate the in vitro results.
Results
LDHA was aberrantly overexpressed in PTC. Intense immunostaining for LDHA was observed in PTC specimens carrying mutated BRAF, whereas the intensity was less in wild-type BRAF samples. Overexpression of BRAFV^600E resulted in LDHA upregulation, whereas treatment with shBRAF downregulated LDHA in human thyroid cell lines. Furthermore, LDHA mRNA expression was significantly elevated and associated with BRAFV^600E expression in thyroid cancer tissues from TCGA database. Additionally, LDHA overexpression was found to be correlated with aggressive clinical features of PTC, such as lymph node metastases and advanced tumor stages.
Conclusion
LDHA overexpression is associated with the BRAFV^600E mutation and an aggressive PTC behavior. Therefore, LDHA may serve as a biomarker and therapeutic target in PTC.

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Integrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Ning Qu, Di Chen, Ben Ma, Lijun Zhang, Qiuping Wang, Yuting Wang, Hongping Wang, Zhaoxian Ni, Wen Wang, Tian Liao, Jun Xiang, Yulong Wang, Shi Jin, Dixin Xue, Weili Wu, Yu Wang, Qinghai Ji, Hui He, Hai-long Piao, Rongliang Shi
Nature Communications.2024;[Epub] CrossRef
Peripheral lymphocytes and lactate dehydrogenase correlate with response and survival in head and neck cancers treated with immune checkpoint inhibitors
Cassie Pan, Qian Vicky Wu, Jenna Voutsinas, Jeffrey J. Houlton, Brittany Barber, Zain H. Rizvi, Emily Marchiano, Neal Futran, George E. Laramore, Jay J. Liao, Upendra Parvathaneni, Renato G. Martins, Jonathan R. Fromm, Cristina P. Rodriguez
Cancer Medicine.2023; 12(8): 9384. CrossRef
LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer
Liang Shi, Rui Duan, Zhenhua Sun, Qiong Jia, Wenyu Wu, Feng Wang, Jianjun Liu, Hao Zhang, Xue Xue
Cell Death & Differentiation.2023; 30(6): 1517. CrossRef
Integrated analysis of circulating and tissue proteomes reveals that fibronectin 1 is a potential biomarker in papillary thyroid cancer
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BMC Cancer.2023;[Epub] CrossRef
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Marianna Aprile, Simona Cataldi, Caterina Perfetto, Antonio Federico, Alfredo Ciccodicola, Valerio Costa
British Journal of Cancer.2023; 129(2): 249. CrossRef
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Cell Death & Disease.2021;[Epub] CrossRef

Review Article

Thyroid
Mechanisms of TERT Reactivation and Its Interaction with BRAF^V600E: Young Shin Song, Young Joo Park; Endocrinol Metab. 2020;35(3):515-525. Published online September 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.304

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The telomerase reverse transcriptase (TERT) gene, which is repressed in most differentiated human cells, can be reactivated by somatic TERT alterations and epigenetic modulations. Moreover, the recruitment, accessibility, and binding of transcription factors also affect the regulation of TERT expression. Reactivated TERT contributes to the development and progression of cancer through telomere lengthening-dependent and independent ways. In particular, because of recent advances in high-throughput sequencing technologies, studies on genomic alterations in various cancers that cause increased TERT transcriptional activity have been actively conducted. TERT reactivation has been reported to be associated with poor prognosis in several cancers, and TERT promoter mutations are among the most potent prognostic markers in thyroid cancer. In particular, when a TERT promoter mutation coexists with the BRAF^V600E mutation, these mutations exert synergistic effects on a poor prognosis. Efforts have been made to uncover the mechanisms of these synergistic interactions. In this review, we discuss the role of TERT reactivation in tumorigenesis, the mechanisms of TERT reactivation across all human cancers and in thyroid cancer, and the mechanisms of interactions between BRAF^V600E and TERT promoter mutations.

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Original Articles

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.

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Cesar Seigi Fuziwara, Diego Claro de Mello, Edna Teruko Kimura
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Extracellular Vesicles as Signal Carriers in Malignant Thyroid Tumors?
Małgorzata Grzanka, Anna Stachurska-Skrodzka, Anna Adamiok-Ostrowska, Ewa Gajda, Barbara Czarnocka
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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

Thyroid
Comparison of Immunohistochemistry and Direct Sanger Sequencing for Detection of the BRAF^V600E Mutation in Thyroid Neoplasm: Hye-Seon Oh, Hyemi Kwon, Suyeon Park, Mijin Kim, Min Ji Jeon, Tae Yong Kim, Young Kee Shong, Won Bae Kim, Jene Choi, Won Gu Kim, Dong Eun Song; Endocrinol Metab. 2018;33(1):62-69. Published online January 30, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.1.62

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Background

The BRAF^V600E mutation is the most common genetic alteration identified in papillary thyroid carcinoma (PTC). Because of its costs effectiveness and sensitivity, direct Sanger sequencing has several limitations. The aim of this study was to evaluate the efficiency of immunohistochemistry (IHC) as an alternative method to detect the BRAF^V600E mutation in preoperative and postoperative tissue samples.

Methods

We evaluated 71 patients who underwent thyroid surgery with the result of direct sequencing of the BRAF^V600E mutation. IHC staining of the BRAF^V600E mutation was performed in 49 preoperative and 23 postoperative thyroid specimens.

Results

Sixty-two patients (87.3%) had PTC, and of these, BRAF^V600E was confirmed by direct sequencing in 57 patients (91.9%). In 23 postoperative tissue samples, the BRAF^V600E mutation was detected in 16 samples (70%) by direct sequencing and 18 samples (78%) by IHC. In 24 fine needle aspiration (FNA) samples, BRAF^V600E was detected in 18 samples (75%) by direct sequencing and 16 samples (67%) by IHC. In 25 core needle biopsy (CNB) samples, the BRAF^V600E mutation was detected in 15 samples (60%) by direct sequencing and 16 samples (64%) by IHC. The sensitivity and specificity of IHC for detecting the BRAF^V600E mutation were 77.8% and 66.7% in FNA samples and 99.3% and 80.0% in CNB samples.

Conclusion

IHC could be an alternative method to direct Sanger sequencing for BRAF^V600E mutation detection both in postoperative and preoperative samples. However, application of IHC to detect the BRAF^V600E mutation in FNA samples is of limited value compared with direct sequencing.

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L. Yu. Zurnadzhy, T.I. Rogounovitch, V.O. Saenko, M.Yu. Bolgov, S.V. Masiuk, S.V. Burko, T.L. Degtyaryova, S.V. Chernyshov, S.V. Gulevatyi, N. Mitsutake, M.D. Tronko, T.I. Bogdanova
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Thyroid
The Frequency and Clinical Implications of the BRAF^V600E Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades: A Ram Hong, Jung Ah Lim, Tae Hyuk Kim, Hoon Sung Choi, Won Sang Yoo, Hye Sook Min, Jae Kyung Won, Kyu Eun Lee, Kyeong Cheon Jung, Do Joon Park, Young Joo Park; Endocrinol Metab. 2014;29(4):505-513. Published online December 29, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.4.505

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Background

Over the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC) as well as a number of changes in the clinicopathological characteristics of this disease. BRAF^V600E, which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAF^V600E mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed.

Methods

The present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAF^V600E mutation status of each patient was confirmed using the polymerase chain reaction-restriction fragment length polymorphism method or by the direct sequencing of DNA.

Results

The prevalence of the BRAF^V600E mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001) over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE) and lymph node metastasis in 2009 to 2012 patients with the BRAF^V600E mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAF^V600E mutation (P=0.047). Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAF^V600E mutation status.

Conclusion

The BRAF^V600E mutation rate in Korean PTC patients has been persistently high (approximately 70%) over the past two decades and continues to increase. The present findings demonstrate that BRAF^V600E-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAF^V600E mutation status may be a useful prognostic factor for PTC in patients recently diagnosed with this disease.

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The Relationship between the BRAF Mutations in Thyroid Papillary Carcinomas and the Prognostic Factors.: So Young Rha, Jun Chul Lee, Ki Hyun Kwon, Hyo Jin Lee, Koon Soon Kim, Young Suk Jo, Bon Jeong Ku, Minho Shong, Young Kun Kim, Heung Kyu Ro; J Korean Endocr Soc. 2005;20(3):224-229. Published online June 1, 2005; DOI: https://doi.org/10.3803/jkes.2005.20.3.224

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BACKGROUND
Thyroid cancers account for about 1% of all human malignancies, with papillary thyroid carcinomas being the most common istotype. Several investigators have recently identified the most common BRAF mutation, the T1796A transversion mutation, in 29~69% of papillary thyroid cancers. The BRAF mutation has been demonstrated as a novel prognostic biomarker for the prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroid invasion and distant metastasis of the tumor. In this study, we investigated the prevalence of the BRAF mutation of thyroid tissues obtained by a thyroidectomy, and its correlation with the clinicopathological outcomes. METHODS: We studied 36 thyroid tissues obtained from 24 women and 12 men by thyroidectomies, including 30 papillary carcinomas, 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia. The mutation was sought in all specimens using DNA sequencing. RESULTS: We studied the BRAF exon 15 T1796A in these 36 thyroid tissues. The mean age at surgery was 46.6, ranging from 18 to 72 years, with a median tumor size of 2.79, ranging from 1.5 to 4.5cm. At the time of diagnosis, 27 of the 34 patients presented with some kind of extrathyroidal invasion of the tumor, and 16 had lymph node metastases. 16, 2 and 16 patients were in stages I, II and III, respectively. There was no distant metastasis. A missense mutation was found at T1796A in exon 15 in 21 of the 30 papillary carcinomas(70%). The other thyroid diseases, including the 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia show no exon 15 T1759A transversion mutation. No statistically significant association was found between the BRAF mutations and clinicopathological characteristics of papillary carcinomas. CONCLUSION: The BRAF mutation is a important genetic alteration, with a high prevalence in papillary thyroid carcinomas. However, there was no significant association between the BRAF mutation and any of the clinicopathological factors. Further, large scale studies will be needed to evaluate the correlation between the BRAF mutation and the clinicopathological factors

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