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

000      

00000naa a2200000 a 4500

001      

bmc22011352

003      

CZ-PrNML

005      

20231121140405.0

007      

ta

008      

220425s2022 xxu f 000 0|eng||

009      

AR

024    7_

$a 10.1093/jnci/djab158 $2 doi

035    __

$a (PubMed)34415331

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxu

100    1_

$a Hadrava Vanova, Katerina $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic

245    10

$a Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma / $c K. Hadrava Vanova, Y. Pang, L. Krobova, M. Kraus, Z. Nahacka, S. Boukalova, SD. Pack, R. Zobalova, J. Zhu, TT. Huynh, I. Jochmanova, O. Uher, S. Hubackova, S. Dvorakova, TJ. Garrett, HK. Ghayee, X. Wu, B. Schuster, PE. Knapp, Z. Frysak, I. Hartmann, N. Nilubol, J. Cerny, D. Taieb, J. Rohlena, J. Neuzil, C. Yang, K. Pacak

520    9_

$a 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.

650    12

$a nádory nadledvin $x genetika $x patologie $7 D000310

650    _2

$a zárodečné mutace $7 D018095

650    _2

$a lidé $7 D006801

650    12

$a paragangliom $x genetika $x patologie $7 D010235

650    12

$a feochromocytom $x genetika $x patologie $7 D010673

650    _2

$a sukcinátdehydrogenasa $x genetika $x metabolismus $7 D013385

655    _2

$a časopisecké články $7 D016428

655    _2

$a Research Support, N.I.H., Intramural $7 D052060

655    _2

$a práce podpořená grantem $7 D013485

700    1_

$a Pang, Ying $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

700    1_

$a Krobova, Linda $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic

700    1_

$a Kraus, Michal $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $u Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic

700    1_

$a Nahacka, Zuzana $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000304772764

700    1_

$a Boukalova, Stepana $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000264784604 $7 xx0129413

700    1_

$a Pack, Svetlana D $u Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA $1 https://orcid.org/0000000332566626

700    1_

$a Zobalová, Renata $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000290974700 $7 xx0310352

700    1_

$a Zhu, Jun $u Systems Biology Center, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, USA

700    1_

$a Huynh, Thanh-Truc $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

700    1_

$a Jochmanova, Ivana $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA $u 1st Department of Internal Medicine, Pavol Jozef Safarik University in Kosice, Faculty of Medicine and Teaching Hospital of Louis Pasteur, Kosice, Slovakia $1 https://orcid.org/000000032346461X

700    1_

$a Uher, Ondrej $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA $u Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice, Czech Republic $1 https://orcid.org/0000000339789822

700    1_

$a Hubackova, Sona $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000234546840

700    1_

$a Dvorakova, Sarka $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000349101008

700    1_

$a Garrett, Timothy J $u Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA $1 https://orcid.org/000000031623009X

700    1_

$a Ghayee, Hans K $u Department of Medicine, Division of Endocrinology, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL, USA $1 https://orcid.org/0000000192013033

700    1_

$a Wu, Xiaolin $u Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA $1 https://orcid.org/0000000264321300

700    1_

$a Schuster, Bjoern $u Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic $1 https://orcid.org/0000000217124718

700    1_

$a Knapp, Philip E $u Section of Endocrinology, Boston Medical Center, Boston University, Boston, MA, USA $1 https://orcid.org/0000000252906125

700    1_

$a Frysak, Zdenek $u 3rd Department of Internal Medicine, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

700    1_

$a Hartmann, Igor $u Department of Urology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic $1 https://orcid.org/0000000294439561 $7 xx0064383

700    1_

$a Nilubol, Naris $u Endocrine Surgery Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA $1 https://orcid.org/0000000273487804

700    1_

$a Cerny, Jiri $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic

700    1_

$a Taieb, David $u Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France

700    1_

$a Rohlena, Jakub $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $1 https://orcid.org/0000000154276502 $7 xx0166966

700    1_

$a Neuzil, Jiri $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic $u School of Pharmacy and Medical Science, Griffith University, Southport, QLD, Australia $1 https://orcid.org/0000000224782460 $7 xx0115772

700    1_

$a Yang, Chunzhang $u Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA $1 https://orcid.org/0000000164330867

700    1_

$a Pacak, Karel $u Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA $1 https://orcid.org/0000000235413767 $7 jo20000074102

773    0_

$w MED00003002 $t Journal of the National Cancer Institute $x 1460-2105 $g Roč. 114, č. 1 (2022), s. 130-138

856    41

$u https://pubmed.ncbi.nlm.nih.gov/34415331 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20220425 $b ABA008

991    __

$a 20231121140402 $b ABA008

999    __

$a ok $b bmc $g 1789103 $s 1162550

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2022 $b 114 $c 1 $d 130-138 $e 20220111 $i 1460-2105 $m Journal of the National Cancer Institute $n J Natl Cancer Inst $x MED00003002

LZP    __

$a Pubmed-20220425