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James F Powers Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

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Brent Cochran Department of Developmental, Molecular and Chemical Biology

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James D Baleja Department of Developmental, Molecular and Chemical Biology

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Hadley D Sikes Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

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Andrew D Pattison Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia

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Xue Zhang Department of Developmental, Molecular and Chemical Biology

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Inna Lomakin Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

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Annette Shepard-Barry Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver Division National Institute of Child Health and Human Development, Bethesda, Maryland, USA

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Sun Jin Moon Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

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Troy F Langford Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

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Kassi Taylor Stein Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

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Richard W Tothill Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Yingbin Ouyang Cyagen US Inc, Santa Clara, California, USA

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Arthur S Tischler Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

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dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . Journal of Clinical Endocrinology and Metabolism 92 3822 – 3828 . ( https://doi.org/10.1210/jc.2007-0709 ) Bechmann N Poser I Seifert V

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Elena Rapizzi Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Rossella Fucci Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Elisa Giannoni Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Letizia Canu Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Susan Richter Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Paolo Cirri Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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Massimo Mannelli Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Endocrinology Unit, Biochemistry Unit, Institute of Clinical Chemistry and Laboratory Medicine, Istituto Toscano Tumori, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

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In solid tumors, neoplastic cells grow in contact with the so-called tumor microenvironment. The interaction between tumor cells and the microenvironment causes reciprocal metabolic reprogramming and favorable conditions for tumor growth and metastatic spread. To obtain an experimental model resembling the in vivo conditions of the succinate dehydrogenase B subunit (SDHB)-mutated paragangliomas (PGLs), we evaluated the effects of SDHB silencing on metabolism and proliferation in the human neuroblastoma cell line (SK-N-AS), cultured alone or in association with human fibroblasts. Silencing caused a 70% decrease in protein expression, an almost complete loss of the complex specific enzymatic activity, and a significant increase in HIF1α and HIF2α expression; it thus resembled the in vivo tumor cell phenotype. When compared with WT SK-N-AS cells, SDHB-silenced cells showed an altered metabolism characterized by an unexpected significant decrease in glucose uptake and an increase in lactate uptake. Moreover, silenced cells exhibited a significant increase in cell proliferation and metalloproteinase activity. When co-cultured with human fibroblasts, control cells displayed a significant decrease in glucose uptake and a significant increase in cell proliferation as compared with their mono-cultured counterparts. These effects were even more evident in co-cultured silenced cells, with a 70% decrease in glucose uptake and a 92% increase in cell proliferation as compared to their mono-cultured counterparts. The present data indicate for the first time, to our knowledge, that SDHB impairment causes metabolic and functional derangement of neural-crest-derived tumor cells and that the microenvironment, here represented by fibroblasts, strongly affects their tumor metabolism and growth capacity.

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Noriko Kimura Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Kazuhiro Takekoshi Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Akira Horii Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Ryo Morimoto Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Tsuneo Imai Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Yutaka Oki Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Tomohito Saito Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Sanae Midorikawa Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Tadashi Arao Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Chiho Sugisawa Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Masanobu Yamada Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Yuichi Otuka Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Isao Kurihara Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Kokichi Sugano Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Minoru Nakane Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Atsushi Fukuuchi Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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Takumi Kitamoto Pathology Division, Department of Clinical Research, National Hospital Organization, Hakodate Hospital, Division of Sports Medicine, Faculty of Medicine, University of Tsukuba, Division of Molecular Pathology, Department of Pathology, School of Medicine, Tohoku University, Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, School of Medicine, Tohoku University, Department of Breast and Endocrine Surgery, Aichi Medical, School of Medicine, Department of Endocrinology and Metabolism, Hamamatsu Medical School, Division of Thoracic Surgery, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical School, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Department of Surgery, Nippon, Telegraph and Telephone East Corporation Medical Center, Department of Internal Medicine, School of Medicine, Keio University, Genetic Counseling Clinic, National Cancer Center, Department of Oncology, Musashino Red Cross Hospital, Department of Breast and Endocrine Surgery, Mitsui Memorial Hospital, Department of Endocrinology and Metabolism, Japan Labour Health and Welfare Organization, Yokohama Rosai Hospital, Department of Endocrinology, Metabolism and Hypertension, National Hospital Organization Kyoto Medical Center, 18-16 Kawahara, Hakodate, Hokkaido, 041-8512, Japan

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-Roqueplo AP 2007 Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . Journal of Clinical Endocrinology and Metabolism 92 3822 – 3828 . ( doi:10.1210/jc.2007-0709 ). Benn DE

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-0033) Srirangalingam U Walker L Khoo B MacDonald F Gardner D Wilkin TJ Skelly RH George E Spooner D Monson JP 2008 Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH

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Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . Journal of Clinical Endocrinology and Metabolism 92 3822 – 3828 . Astrom K Cohen JE Willett-Brozick JE Aston CE Baysal

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.1210/jc.2004-1398 ). Amar L Baudin E Burnichon N Peyrard S Silvera S Bertherat J Bertagna X Schlumberger M Jeunemaitre X Gimenez-Roqueplo AP 2007 Succinate dehydrogenase B gene mutations predict survival in patients with malignant

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for succinate dehydrogenase B, C, and D mutations. The primary tumor was found in the urinary bladder and was removed with en bloc cystectomy, prostatectomy, with lymphatic node dissection and creation of ileal neobladder in 2005. In 2009, he was

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Taylor C Brown Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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James M Healy Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
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Reju Korah Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
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Tobias Carling Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Catharina Larsson Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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biological evidence of metastatic disease according to the current WHO criteria. Relationship between C228T and molecular phenotypes Mutation of the succinate dehydrogenase B gene ( SDHB ) is a frequent genetic event in PGL, especially in malignant PGL

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X Schlumberger M Jeunemaitre X Gimenez-Roqueplo AP 2007 Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . Journal of Clinical Endocrinology and Metabolism 92 3822

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of Clinical Oncology 23 8812 – 8818 . Amar L Baudin E Burnichon N Peyrard S Silvera S Bertherat J Bertagna X Schlumberger M Jeunemaitre X Gimenez-Roqueplo AP 2007 Succinate dehydrogenase B gene mutations predict survival in

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