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.

1st Department of Internal Medicine Pavol Jozef Safarik University in Kosice Faculty of Medicine and Teaching Hospital of Louis Pasteur Kosice Slovakia

3rd Department of Internal Medicine University Hospital and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Cancer Research Technology Program Frederick National Laboratory for Cancer Research Frederick MD USA

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Department of Medicine Division of Endocrinology Malcom Randall VA Medical Center University of Florida Gainesville FL USA

Department of Nuclear Medicine La Timone University Hospital CERIMED Aix Marseille University Marseille France

Department of Urology University Hospital Olomouc and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Endocrine Surgery Section Surgical Oncology Program National Cancer Institute National Institutes of Health Bethesda MD USA

Institute of Biotechnology Czech Academy of Sciences BIOCEV Vestec Prague West Czech Republic

Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic

Laboratory of Pathology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

Neuro Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

School of Pharmacy and Medical Science Griffith University Southport QLD Australia

Section of Endocrinology Boston Medical Center Boston University Boston MA USA

Section of Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA

Southeast Center for Integrated Metabolomics Clinical and Translational Science Institute University of Florida Gainesville FL USA

Systems Biology Center National Heart Lung Blood Institute National Institutes of Health Bethesda MD USA

J Natl Cancer Inst. 2022 Jan 11;114(1):7-8. doi: 10.1093/jnci/djab160. PubMed

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