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WRN-MSI Pan-Cancer Atlas — Mitochondrial/OXPHOS Enrichment Analysis
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Pan-cancer MSI-H gained dependencies: 181 genes (FDR<0.05, d<-0.5)
Mitochondrial genes in gained deps: 33/181 (18.2%)
Expected by chance: 11.5 (MitoCarta ~1,136 / 17,931 tested)
Enrichment: 2.9-fold
Fisher's exact test OR=3.37, p=3.32e-08

OXPHOS COMPLEX BREAKDOWN
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  Complex I (NADH dehydrogenase):    5 genes, avg d=-0.604
  Complex II (SDH):                  2 genes, avg d=-0.634
  Complex III (ubiquinol-cyt c):     2 genes, avg d=-0.622
  Complex IV (cytochrome c oxidase): 6 genes, avg d=-0.618
  Mitochondrial ribosome:           15 genes, avg d=-0.599
  Mito transcription/replication:    2 genes, avg d=-0.704
  TCA cycle:                         1 gene,  avg d=-0.772

INTERPRETATION
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MSI-H tumors show systematic dependency on mitochondrial function,
spanning all 5 OXPHOS complexes plus mitochondrial translation/replication.
This suggests metabolic reprogramming toward OXPHOS reliance in MSI-H cells.

Possible mechanism: MMR deficiency may impair nuclear-encoded mitochondrial
gene expression or mtDNA stability, creating synthetic dependency on
remaining mitochondrial function. Alternatively, MSI-H cells may shift
toward OXPHOS to compensate for glycolytic impairment from frameshift
mutations in metabolic enzymes.

THERAPEUTIC IMPLICATIONS
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OXPHOS inhibitors as WRN inhibitor combination partners:
  - IACS-010759 (Complex I inhibitor) — clinical development halted but proof of concept
  - Metformin (weak Complex I inhibitor) — repurposing candidate, favorable safety
  - Venetoclax (indirect OXPHOS inhibition) — approved in AML
  - Mubritinib (Complex I) — preclinical

WRN inhibitor + OXPHOS inhibitor could exploit dual synthetic lethality:
  1. WRN inhibitor → replication stress from expanded microsatellites
  2. OXPHOS inhibitor → metabolic crisis from mitochondrial dependency
