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  • Germline SUCLG2 Variants in Patients with Pheochromocytoma and Paraganglioma

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    Neuzil510280-Accepted.pdf (870.8Kb)
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    Accepted Manuscript (AM)
    Author(s)
    Vanova, Katerina Hadrava
    Pang, Ying
    Krobova, Linda
    Kraus, Michal
    Nahacka, Zuzana
    Boukalova, Stepana
    Pack, Svetlana D
    Zobalova, Renata
    Zhu, Jun
    Huynh, Thanh-Truc
    Jochmanova, Ivana
    Uher, Ondrej
    Hubackova, Sona
    Neuzil, Jiri
    et al.
    Griffith University Author(s)
    Neuzil, Jiri
    Year published
    2021
    Metadata
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    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 subjects 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 ...
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    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 subjects 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 eight germline variants in the GTP-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 CII and faulty assembly of the complex, 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.
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    Journal Title
    JNCI: Journal of the National Cancer Institute
    DOI
    https://doi.org/10.1093/jnci/djab158
    Copyright Statement
    © 2021 Oxford University Press. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Journal of the National Cancer Institute (JNCI) following peer review. The definitive publisher-authenticated version Germline SUCLG2 Variants in Patients with Pheochromocytoma and Paraganglioma , Journal of the National Cancer Institute (JNCI), 2021 is available online at: https://doi.org/10.1093/jnci/djab158
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Oncology and carcinogenesis
    Publication URI
    http://hdl.handle.net/10072/407478
    Collection
    • Journal articles

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