Hadrava Vanova Katerina, 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, Dvorakova Sarka, Garrett Timothy J, Ghayee Hans K, Wu Xiaolin, Schuster Bjoern, Knapp Philip E, Frysak Zdenek, Hartmann Igor, Nilubol Naris, Cerny Jiri, Taieb David, Rohlena Jakub, Neuzil Jiri, Yang Chunzhang, Pacak Karel
Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec, Prague West, Czech Republic.
J Natl Cancer Inst. 2022 Jan 11;114(1):130-138. doi: 10.1093/jnci/djab158.
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.
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.
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.
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.
嗜铬细胞瘤和副神经节瘤（PPGL）是神经内分泌肿瘤，与三羧酸循环相关的基因频繁发生突变。然而，迄今为止，在琥珀酰辅酶A连接酶（SUCL）中尚未发现致病变异，该酶为琥珀酸脱氢酶（SDH；线粒体复合物II [CII]）提供底物，而SDH是PPGL中已知的肿瘤抑制因子。
对352例明显散发型PPGL患者进行队列研究，使用美国国立卫生研究院开发的包含54个基因的基因检测面板进行检测，其中包括SUCL的SUCLG2亚基。在可能的情况下，对肿瘤中的基因缺失、琥珀酸水平和蛋白质水平进行评估。为了确认可能的机制，我们使用了源自人嗜铬细胞瘤的祖细胞系hPheo1，并敲除和重新表达SUCLG2。
我们在15例（352例中的15例，4.3%）明显散发型PPGL患者的SUCLG2鸟苷三磷酸结合结构域中描述了8个种系变体。对SUCLG2突变肿瘤和SUCLG2缺陷的hPheo1细胞的分析显示，SUCLG2蛋白缺失，SDH的SDHB亚基水平降低，复合物II组装错误，导致呼吸异常和琥珀酸积累增加。
我们的研究表明SUCLG2是PPGL遗传图谱中的一个新候选基因。大规模测序可能会发现更多携带SUCLG2变体的病例，并提供有关其患病率和外显率的更详细信息。
