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Analyzing Genetic Differences Between Sporadic Primary and Secondary/Tertiary Hyperparathyroidism by Targeted Next-Generation Panel Sequencing

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Abstract

Secondary hyperparathyroidism (SHPT) is characterized by excessive serum parathyroid hormone levels in response to decreasing kidney function, and tertiary hyperparathyroidism (THPT) is often the result of a long-standing SHPT. To date, several genes have been associated with the pathogenesis of primary hyperparathyroidism (PHPT). However, the molecular genetic mechanisms of uremic hyperparathyroidism (HPT) remain uncharacterized. To elucidate the differences in genetic alterations between PHPT and SHPT/THPT, the targeted next-generation sequencing of genes associated with HPT was performed using DNA extracted from parathyroid tissues. As a result, 26 variants in 19 PHPT or SHPT/THPT appeared as candidate pathogenic mutations, which corresponded to 9 (35%) nonsense, 8 (31%) frameshift, 6 (23%) missense, and 3 (11%) splice site mutations. The MEN1 (23%, 6/26), ASXL3 (15%, 4/26), EZH2 (12%, 3/26), and MTOR (8%, 2/26) genes were frequently mutated. Sixteen of 25 patients with PHPT (64%) had one or more mutations, whereas 3 (21%) of 21 patients with SHPT/THPT had only 1 mutation (p = 0.001). Sixteen of 28 patients (57%) with parathyroid adenoma (PA) had one or more mutations, whereas 3 of 18 patients (17%) with parathyroid hyperplasia (PH) had just one mutation (p = 0.003). Known driver mutations associated with parathyroid tumorigenesis such as CCND1/PRAD1, CDC73/HRPT2, and MEN1 were identified only in PA (44%, 7/16 with mutations). Our results suggest that molecular genetic abnormalities in SHPT/THPT are distinct from those in PHPT. These findings may help in analyzing the molecular pathogenesis underlying uremic HPT development.

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Acknowledgements

We would like to specially thank Mr. Taekyu Lee from Thermo Fisher Scientific for his contribution in providing technical support with the Ion Torrent NGS experiments.

Funding

This work was supported by a National Research Foundation of Korea (NRF) grant, funded by the Korean government (MSIT) (No. 2018R1C1B5045006), and a Clinical Research Institute Grant funded by the Catholic University of Korea Daejeon St. Mary’s Hospital (CMCDJ-P-2020–012).

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Yu Ah Hong, Won Jung Choi, Yoon-Kyung Chang & Suk Young Kim

  2. Clinical Research Institute, Daejeon St. Mary’s Hospital, Daejeon, Republic of Korea

    Ki Cheol Park

  3. Division of Breast and Thyroid Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Bong Kyun Kim, Jina Lee & Woo Young Sun

  4. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Hae Joung Sul

  5. Department of Research and Development, SML Genetree, Seoul, Republic of Korea

    Kyung-Ah Hwang

  6. Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Soyoung Shin

  7. Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, Jeonju, Republic of Korea

    Joonhong Park

  8. Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea

    Joonhong Park

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Contributions

YAH designed the study and wrote the first draft of the manuscript. BKK, JL, and WYS participated in data collection. KCP contributed to sample preparation. WJC, YKC, and SYK interpreted the data. SS and JP performed molecular experiments and interpreted the sequencing data. KYH contributed to mRNA gene expression analysis. YAH and JP reviewed/edited the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Joonhong Park.

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The study protocol was approved by the Institutional Review Board of The Catholic University of Korea (DC19SESI0016). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

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Hong, Y.A., Park, K.C., Kim, B.K. et al. Analyzing Genetic Differences Between Sporadic Primary and Secondary/Tertiary Hyperparathyroidism by Targeted Next-Generation Panel Sequencing. Endocr Pathol 32, 501–512 (2021). https://doi.org/10.1007/s12022-021-09686-x

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