Succinate dehydrogenase (Complex II / SDH) is unique among TCA cycle enzymes because it is also an integral component of the ETC. SDH is encoded entirely by nuclear DNA. Germline mutations in SDHB, SDHC, or SDHD subunits predispose to which specific tumours?

• A Adrenocortical carcinoma and pheochromocytoma only
• B Hepatocellular carcinoma and renal cell carcinoma
• C Paraganglioma and pheochromocytoma (PPGL syndrome) ✓
• D Thyroid carcinoma and medullary thyroid cancer

Explanation

Germline mutations in SDH subunit genes (SDHA, SDHB, SDHC, SDHD) cause hereditary paraganglioma-pheochromocytoma (PPGL) syndrome. SDHB mutations have the highest malignancy risk (~50% malignant paraganglioma). SDH loss leads to succinate accumulation, which competitively inhibits alpha-ketoglutarate-dependent dioxygenases (including HIF prolyl hydroxylases and TET demethylases), causing pseudo-hypoxic HIF activation and altered DNA methylation — the 'oncometabolite' mechanism. SDHB is the most clinically significant subunit due to risk of metastasis.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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