Katerina Hadrava Vanova1,2, Ying Pang1, Linda Krobova2, Michal Kraus2,3, Zuzana Nahacka2, Stepana Boukalova2, Svetlana D Pack4, Renata Zobalova2, Jun Zhu5, Thanh-Truc Huynh1, Ivana Jochmanova1,6, Ondrej Uher1,7, Sona Hubackova2, Sarka Dvorakova2, Timothy J Garrett8, Hans K Ghayee9, Xiaolin Wu10, Bjoern Schuster11, Philip E Knapp12, Zdenek Frysak13, Igor Hartmann14, Naris Nilubol15, Jiri Cerny2, David Taieb16, Jakub Rohlena2, Jiri Neuzil2,17, Chunzhang Yang18, Karel Pacak1. 1. Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 2. Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic. 3. Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic. 4. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 5. Systems Biology Center, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, USA. 6. 1st Department of Internal Medicine, Pavol Jozef Safarik University in Kosice, Faculty of Medicine and Teaching Hospital of Louis Pasteur, Kosice, Slovakia. 7. Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice, Czech Republic. 8. Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. 9. Department of Medicine, Division of Endocrinology, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL, USA. 10. Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 11. Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic. 12. Section of Endocrinology, Boston Medical Center, Boston University, Boston, MA, USA. 13. 3rd Department of Internal Medicine, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. 14. Department of Urology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. 15. Endocrine Surgery Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 16. Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France. 17. School of Pharmacy and Medical Science, Griffith University, Southport, QLD, Australia. 18. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract
BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. METHODS: A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. RESULTS: We describe 8 germline variants in the guanosine triphosphate-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. CONCLUSIONS: Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance. Published by Oxford University Press 2021. This work is written by a US Government employee and is in the public domain in the US.
BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. METHODS: A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. RESULTS: We describe 8 germline variants in the guanosine triphosphate-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. CONCLUSIONS: Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance. Published by Oxford University Press 2021. This work is written by a US Government employee and is in the public domain in the US.
Authors: Hartmut P H Neumann; Birke Bausch; Sarah R McWhinney; Bernhard U Bender; Oliver Gimm; Gerlind Franke; Joerg Schipper; Joachim Klisch; Carsten Altehoefer; Klaus Zerres; Andrzej Januszewicz; Charis Eng; Wendy M Smith; Robin Munk; Tanja Manz; Sven Glaesker; Thomas W Apel; Markus Treier; Martin Reineke; Martin K Walz; Cuong Hoang-Vu; Michael Brauckhoff; Andreas Klein-Franke; Peter Klose; Heinrich Schmidt; Margarete Maier-Woelfle; Mariola Peçzkowska; Cesary Szmigielski; Charis Eng Journal: N Engl J Med Date: 2002-05-09 Impact factor: 91.245
Authors: Lauren Fishbein; Ignaty Leshchiner; Vonn Walter; Ludmila Danilova; A Gordon Robertson; Amy R Johnson; Tara M Lichtenberg; Bradley A Murray; Hans K Ghayee; Tobias Else; Shiyun Ling; Stuart R Jefferys; Aguirre A de Cubas; Brandon Wenz; Esther Korpershoek; Antonio L Amelio; Liza Makowski; W Kimryn Rathmell; Anne-Paule Gimenez-Roqueplo; Thomas J Giordano; Sylvia L Asa; Arthur S Tischler; Karel Pacak; Katherine L Nathanson; Matthew D Wilkerson Journal: Cancer Cell Date: 2017-02-02 Impact factor: 31.743
Authors: Alberto Cascón; Iñaki Comino-Méndez; María Currás-Freixes; Aguirre A de Cubas; Laura Contreras; Susan Richter; Mirko Peitzsch; Veronika Mancikova; Lucía Inglada-Pérez; Andrés Pérez-Barrios; María Calatayud; Sharona Azriel; Rosa Villar-Vicente; Javier Aller; Fernando Setién; Sebastian Moran; Juan F Garcia; Ana Río-Machín; Rocío Letón; Álvaro Gómez-Graña; María Apellániz-Ruiz; Giovanna Roncador; Manel Esteller; Cristina Rodríguez-Antona; Jorgina Satrústegui; Graeme Eisenhofer; Miguel Urioste; Mercedes Robledo Journal: J Natl Cancer Inst Date: 2015-03-11 Impact factor: 13.506
Authors: Paul Benjamin Loughrey; Federico Roncaroli; Estelle Healy; Philip Weir; Madhu Basetti; Ruth T Casey; Steven J Hunter; Márta Korbonits Journal: Endocr Relat Cancer Date: 2022-09-02 Impact factor: 5.900