Co-authored by BSI’s Bob Kaplan, this review examines hereditary cancer syndromes through a metabolic lens, arguing that inherited gene mutations increase cancer risk primarily by impairing mitochondrial oxidative phosphorylation rather than acting as direct genetic causes. Surveying more than a dozen well-characterized syndromes, the authors show that none are fully penetrant and that nearly all are associated with mitochondrial dysfunction, oxidative stress, and a shift toward substrate-level phosphorylation—core features of the mitochondrial metabolic theory of cancer.

From this perspective, inherited mutations function as secondary risk factors that destabilize cellular energy production, creating conditions that permit malignant transformation. The authors conclude that cancer risk in hereditary syndromes may be biologically modifiable through interventions that support mitochondrial function, rather than an unavoidable genetic outcome.