SDHB

Overview

SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) encodes the iron-sulfur subunit of the mitochondrial succinate dehydrogenase complex (complex II), linking the Krebs cycle to the electron transport chain. Germline loss-of-function mutations in SDHB are among the most common hereditary drivers of pheochromocytoma (PCC) and paraganglioma (PGL), defining the pseudohypoxia molecular subtype. SDHB germline carriers are at substantially elevated risk for aggressive, metastatic disease.

Alterations observed in the corpus

  • Germline pathogenic mutations present in 9% of the 173-patient TCGA PCC/PGL cohort (pcpg_tcga_pub), the most frequent germline susceptibility gene; mutations are specific to the pseudohypoxia mRNA subtype. PMID:28162975
  • SDHB germline mutations co-occur with somatic ATRX mutations in 3 tumors; ATRX co-mutation marks alternative lengthening of telomeres and aggressive disease. PMID:28162975
  • SDHB germline status associates with the hypermethylated DNA methylation subtype and with worse aggressive-disease-free survival (ADFS) and metastatic-free survival (MFS). PMID:28162975

Cancer types (linked)

  • PHC / PGNG: Germline SDHB mutation is the leading hereditary driver; the pseudohypoxia subtype was enriched for genome-doubling (74% of most-doubled tumors) and hypermethylation. SDHB germline is a significant negative marker for both ADFS and MFS. PMID:28162975

Co-occurrence and mutual exclusivity

  • Co-occurs with somatic ATRX mutations in 3 PCC/PGL tumors; otherwise driver mutations in the 21-gene susceptibility set were strikingly mutually exclusive (p < 1e-4). PMID:28162975
  • Mutually exclusive with RET, VHL, NF1, SDHD, MAX, EGLN1, TMEM127 germline events in the same cohort. PMID:28162975

Therapeutic relevance

  • SDH-mutant tumors accumulate glutamine; the authors propose glutaminase inhibitors (e.g., NCT02071862) as a therapeutic strategy. PMID:28162975
  • ATRX-loss tumors (enriched in SDHB-germline cases) may be sensitive to ATR inhibitors (hypothesis only, not tested). PMID:28162975

Open questions

  • Whether ATRX-co-mutant SDHB-germline tumors represent a clinically distinct subset warranting ATR-inhibitor trials requires prospective study. PMID:28162975

Sources

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