{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSuccinate dehydrogenase subunit C (SDHC) is an essential component of the mitochondrial complex II that bridges the tricarboxylic acid cycle and the electron transport chain. SDHC, along with the other subunits, mediates the oxidation of succinate to fumarate and plays a critical role in cellular energy production. Loss‐of‐function mutations or epimutations affecting SDHC disturb this metabolic process, leading to the accumulation of succinate—an oncometabolite that can inhibit α‐ketoglutarate–dependent dioxygenases and promote tumorigenesis. In several neoplasms such as gastrointestinal stromal tumors (GISTs), paragangliomas, and other inherited neoplasia syndromes, germline and somatic defects in SDHC have been implicated as drivers of disease when classical oncogenic mutations (e.g., in KIT or PDGFRA) are absent."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to genetic mutations, epigenetic inactivation of SDHC—such as promoter-specific CpG island hypermethylation—has been identified in distinct tumor subtypes, including SDH‐deficient GISTs seen in Carney triad and related syndromes. These alterations lead to reduced mRNA and protein expression of SDHC, resulting in complex II dysfunction and further accumulation of oncometabolites. The resultant metabolic imbalance contributes not only to aberrant cellular signaling through pathways such as hypoxia-inducible factor stabilization but is also diagnostically useful via immunohistochemical detection of SDHB loss as a proxy for overall SDH dysfunction. Such mechanisms underscore the role of SDHC both as a classical tumor suppressor gene and as a nodal point in the metabolic reprogramming of tumor cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, SDHC alterations are associated with a spectrum of neoplasms that display varied tumor behaviors, ranging from benign head and neck paragangliomas to malignant presentations in other sites such as renal cell carcinomas and pheochromocytomas. Experimental models have demonstrated that SDHC mutations can lead to increased reactive oxygen species production, mitochondrial dysfunction, and genomic instability, thereby reinforcing the pathogenic role of SDHC loss in tumor development. The diagnostic utility of screening for SDHC mutations and aberrant expression patterns is increasingly recognized, offering opportunities for targeted genetic counseling and potential therapeutic intervention aimed at restoring metabolic balance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Barbara Pasini, Sarah R McWhinney, Thalia Bei, et al. 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