Endocrinology and Metabolism

Original Articles

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

Citations to this article as recorded by

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
Case Report: Aggressive neural crest tumors in a child with familial von Hippel Lindau syndrome associated with a germline VHL mutation (c.414A>G) and a novel KIF1B gene mutation
Lucie Landen, Anne De Leener, Manon Le Roux, Bénédicte Brichard, Selda Aydin, Dominique Maiter, Philippe A. Lysy
Frontiers in Endocrinology.2023;[Epub] CrossRef
A Case of Pheochromocytoma as a Subsequent Neoplasm in a Survivor of Childhood Embryonal Rhabdomyosarcoma
Rozalyn L. Rodwin, Sanyukta K. Janardan, Erin W. Hofstatter, Nina S. Kadan-Lottick
Journal of Pediatric Hematology/Oncology.2022; 44(2): e585. CrossRef
Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma
Chik Hong Kuick, Jia Ying Tan, Deborah Jasmine, Tohari Sumanty, Alvin Y. J. Ng, Byrrappa Venkatesh, Huiyi Chen, Eva Loh, Sudhanshi Jain, Wan Yi Seow, Eileen H. Q. Ng, Derrick W. Q. Lian, Shui Yen Soh, Kenneth T. E. Chang, Zhi Xiong Chen, Amos H. P. Loh
BMC Cancer.2022;[Epub] CrossRef
A case of juvenile-onset pheochromocytoma with KIF1B p.V1529M germline mutation
Masahiro Nezu, Yosuke Hirotsu, Kenji Amemiya, Miho Katsumata, Tomomi Watanabe, Soichi Takizawa, Masaharu Inoue, Hitoshi Mochizuki, Kyoko Hosaka, Toshio Oyama, Masao Omata
Endocrine Journal.2022; 69(6): 705. CrossRef
Systematic analysis of expression profiles and prognostic significance for MMDS-related iron–sulfur proteins in renal clear cell carcinoma
Ling Yang, Yu-Xin Chen, Ying-Ying Li, Xiao-Juan Liu, Yong-Mei Jiang, Jia Mai
Scientific Reports.2022;[Epub] CrossRef
Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force
Eu Jeong Ku, Kyoung Jin Kim, Jung Hee Kim, Mi Kyung Kim, Chang Ho Ahn, Kyung Ae Lee, Seung Hun Lee, You-Bin Lee, Kyeong Hye Park, Yun Mi Choi, Namki Hong, A Ram Hong, Sang-Wook Kang, Byung Kwan Park, Moon-Woo Seong, Myungshin Kim, Kyeong Cheon Jung, Chan
Endocrinology and Metabolism.2021; 36(2): 322. CrossRef
Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas
Yinjie Gao, Chao Ling, Xiaosen Ma, Huiping Wang, Yunying Cui, Min Nie, Anli Tong, Dario De Biase
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.

Citations

Citations to this article as recorded by

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
Novel and recurrent genetic variants of VHL, SDHB, and RET genes in Chinese pheochromocytoma and paraganglioma patients
Chong Li, Jingyi Li, Chao Han, Ting Wang, Lixia Zhang, Zhifang Wang, Tingting Wang, Lijun Xu, Guangzhao Qi, Guijun Qin, Xialian Li, Lili Zheng
Frontiers in Genetics.2023;[Epub] CrossRef
Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?
Marta Araujo-Castro, César Mínguez Ojeda, Iñigo García Sanz, Maria Calatayud, Felicia Hanzu, Mireia Mora, Almudena Vicente, Concepción Blanco Carrera, Paz de Miguel Novoa, María del Carmen López García, Cristina Lamas, Laura Manjón-Miguélez, María del Cas
Neuroendocrinology.2023; 113(6): 657. CrossRef
The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis
Petra Hudler, Mojca Urbancic
Genes.2022; 13(2): 362. CrossRef
Bilateral Pheochromocytoma with Germline MAX Variant without Family History
Shinnosuke Hata, Mai Asano, Hiroyuki Tominaga, Masahide Hamaguchi, Fumiya Hongo, Takeshi Usui, Eiichi Konishi, Michiaki Fukui
Clinics and Practice.2022; 12(3): 299. CrossRef
Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force
Eu Jeong Ku, Kyoung Jin Kim, Jung Hee Kim, Mi Kyung Kim, Chang Ho Ahn, Kyung Ae Lee, Seung Hun Lee, You-Bin Lee, Kyeong Hye Park, Yun Mi Choi, Namki Hong, A Ram Hong, Sang-Wook Kang, Byung Kwan Park, Moon-Woo Seong, Myungshin Kim, Kyeong Cheon Jung, Chan
Endocrinology and Metabolism.2021; 36(2): 322. CrossRef
Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma
Masato Yonamine, Koichiro Wasano, Yuichi Aita, Takehito Sugasawa, Katsutoshi Takahashi, Yasushi Kawakami, Hitoshi Shimano, Hiroyuki Nishiyama, Hisato Hara, Mitsuhide Naruse, Takahiro Okamoto, Tadashi Matsuda, Shinji Kosugi, Kazuhiko Horiguchi, Akiyo Tanab
Cancers.2021; 13(16): 4014. CrossRef
Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas
Yinjie Gao, Chao Ling, Xiaosen Ma, Huiping Wang, Yunying Cui, Min Nie, Anli Tong, Dario De Biase
International Journal of Endocrinology.2021; 2021: 1. CrossRef

Genetic and Epigenetic Analysis in Korean Patients with Multiple Endocrine Neoplasia Type 1: Yoon Jung Chung, Sena Hwang, Jong Ju Jeong, Sun Yong Song, Se Hoon Kim, Yumie Rhee; Endocrinol Metab. 2014;29(3):270-279. Published online September 25, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.3.270

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Background

Multiple endocrine neoplasia type 1 (MEN1) is a familial syndrome characterized by the parathyroid, pancreas and pituitary tumors. Parathyroid tumors are the most common clinical manifestations, occurring in more than 90% of MEN1 patients. Heterozygous germline mutations of the MENIN gene underlie the tumorigenesis in MEN1 and epigenetic alterations along with germline mutations may contribute to tumorigenesis. Here, we investigated the associations between genotype and phenotype in Korean MEN1 patients.

Methods

We analyzed medical records from 14 unrelated MEN1 patients who had newly confirmed MENIN germline mutations, together with 14 previous reports in Korea. Aberrant DNA methylations were also examined in MEN1-related parathyroid tumors using the Infinium HumanMethylation 450 BeadChip.

Results

Total 28 germline mutations of MENIN were relatively highly concentrated in exons 7 and 8 compared to previous reports from Western countries. Six mutations (c.111dupT/p.S38Ffs^*79, c.225_226insT/p.T76Yfs^*41, c.383_398del16/p.S128Tfs^*52, c.746dupT/p.H250Afs^*20, c.1150G>T/p.E384^*, and c.1508G>A/p.G503N) were newly found in the present study. Of interest, four patients (15%) showed unusual initial presentations and three patients were diagnosed incidentally at the general medical checkup. We also found three distinct sites in exon 2 of MENIN were significantly hypomethylated in the MEN1 parathyroid tumors, comparing correspondent blood samples.

Conclusion

We also have found a lack of genotype/phenotype correlation in Korean MEN1 patients. There were not a few unusual initial manifestations in MEN1 patients, thus, genetic testing for the MENIN germline mutations can provide important information for the better prognosis. Further studies are warranted to investigate altered DNA methylations in the MENIN gene involved in tumorigenesis.

Citations

Citations to this article as recorded by

Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome
Laura Pierotti, Elena Pardi, Elisa Dinoi, Paolo Piaggi, Simona Borsari, Simone Della Valentina, Chiara Sardella, Angela Michelucci, Maria Adelaide Caligo, Fausto Bogazzi, Claudio Marcocci, Filomena Cetani
Frontiers in Endocrinology.2023;[Epub] CrossRef
A Case of Asymptomatic Multiple Endocrine Neoplasia Type I with Thymic Carcinoid
Suk Ki Park, Moon Won Lee, In Sub Han, Young Joo Park, Sung Yong Han, Joon Woo Park, Bong Eun Lee, Gwang Ha Kim, Sang Soo Kim
The Korean Journal of Helicobacter and Upper Gastrointestinal Research.2019; 19(1): 65. CrossRef
Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives
Fatemeh Khatami, Seyed Mohammad Tavangar
Biomarker Insights.2018; 13: 117727191878512. CrossRef
Articles in 'Endocrinology and Metabolism' in 2014
Won-Young Lee
Endocrinology and Metabolism.2015; 30(1): 47. CrossRef

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