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Article

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma

1
Laboratory of Laboratory/Sports Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan
2
Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro 152-8902, Tokyo, Japan
3
Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan
4
Division of Metabolism, Showa General Hospital, 8-1-1 Hanakoganei, Kodaira 187-8510, Tokyo, Japan
5
Department of Urology, Faculty of Medicine, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba 305-8576, Ibaraki, Japan
6
Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan
7
Institute of Clinical Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusamukaihatacho, Fushimi-ku 612-8555, Kyoto, Japan
8
Endocrine Center and Clinical Research Center, Ijinkai Takeda General Hospital, 28-1 Ishidamoriminamicho, Fushimi-ku 601-1495, Kyoto, Japan
9
Department of Breast and Endocrine Surgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shin-juku-ku 162-8666, Tokyo, Japan
10
Department of Urology and Andrology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Osaka, Japan
11
Department of Medical Ethics/Medical Genetics, Kyoto University School of Public Health, Yoshidakonoecho, Sakyo-ku 606-8501, Kyoto, Japan
12
Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Gunma, Japan
13
Department of Diabetes, Endocrinology and Metabolism, Center Hospital of the National Center for Global-Health and Medicine, 1-21-1 Toyama, Shinjuku-ku 162-8855, Tokyo, Japan
14
Division of Clinical Genetics, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa 920-8641, Ishikawa, Japan
15
Department of Pathology, National Hospital Organization Hakodate National Hospital, 18-16 Kawahara-cho, Hakodate 041-8512, Hokkaido, Japan
16
Department of Urology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo City 104-0045, Tokyo, Japan
17
Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 17-chome Chuo-ku, Sapporo 060-8556, Hokkaido, Japan
18
Department of Head and Neck Surgery, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yaha-ba-cho, Shiwa-gun 028-3695, Iwate, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Enzo Lalli
Cancers 2021, 13(16), 4014; https://doi.org/10.3390/cancers13164014
Received: 25 July 2021 / Revised: 2 August 2021 / Accepted: 4 August 2021 / Published: 9 August 2021
(This article belongs to the Special Issue Research Update on Pheochromocytoma and Paraganglioma)
Pheochromocytoma/paraganglioma (PPGL) has been recognised as one of the most frequent inherited tumours with genetic heterogeneity based on studies in Caucasian populations. Early identification of germline variants is crucial for accurate treatment and follow-up in affected patients and relatives. However, there are only a few large cohort studies in Asia and none from the Japanese population. In this first comprehensive study of Japanese patients with PPGL, we found one in four PPGLs with apparently sporadic presentation harboured germline variant in any of the seven susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET). SDHB was the most frequently mutated gene and was strongly associated with metastatic PPGLs. Our findings emphasise the importance of genetic testing in determining appropriate treatment and follow-up strategies for patients and relatives.
The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population. View Full-Text
Keywords: pheochromocytoma; paraganglioma; genetics; germline variants; Japanese; SDHB; SDHD; VHL pheochromocytoma; paraganglioma; genetics; germline variants; Japanese; SDHB; SDHD; VHL
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MDPI and ACS Style

Yonamine, M.; Wasano, K.; Aita, Y.; Sugasawa, T.; Takahashi, K.; Kawakami, Y.; Shimano, H.; Nishiyama, H.; Hara, H.; Naruse, M.; Okamoto, T.; Matsuda, T.; Kosugi, S.; Horiguchi, K.; Tanabe, A.; Watanabe, A.; Kimura, N.; Nakamura, E.; Sakurai, A.; Shiga, K.; Takekoshi, K. Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma. Cancers 2021, 13, 4014. https://doi.org/10.3390/cancers13164014

AMA Style

Yonamine M, Wasano K, Aita Y, Sugasawa T, Takahashi K, Kawakami Y, Shimano H, Nishiyama H, Hara H, Naruse M, Okamoto T, Matsuda T, Kosugi S, Horiguchi K, Tanabe A, Watanabe A, Kimura N, Nakamura E, Sakurai A, Shiga K, Takekoshi K. Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma. Cancers. 2021; 13(16):4014. https://doi.org/10.3390/cancers13164014

Chicago/Turabian Style

Yonamine, Masato, 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 Tanabe, Atsushi Watanabe, Noriko Kimura, Eijiro Nakamura, Akihiro Sakurai, Kiyoto Shiga, and Kazuhiro Takekoshi. 2021. "Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma" Cancers 13, no. 16: 4014. https://doi.org/10.3390/cancers13164014

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