In this BSI Journal Club, Bob Kaplan and Pete Shaw explore cancer through a metabolic lens, focusing on the normal physiological roles of hereditary cancer syndrome (HCS) genes. Rather than acting primarily as drivers of cancer through mutation, these genes are presented as central to mitochondrial function, oxidative phosphorylation (OXPHOS), and cellular energy regulation. Drawing on recent literature—including Kaplan’s 2025 paper linking hereditary cancer syndromes to oxidative phosphorylation insufficiency—they suggest that mitochondrial dysfunction may precede many of the genetic alterations associated with cancer. Evidence from exercise physiology studies also shows that genes such as BRCA1 and p53 help maintain mitochondrial performance and genomic stability during energetic stress.

Bob and Pete also discuss how the naming and study of cancer genes have biased research toward their mutated forms, leaving their normal roles underexplored. They connect this perspective to the atavistic theory of cancer, which proposes that cancer reflects a reversion to primitive metabolic programs characterized by fermentation and substrate-level phosphorylation. In this framework, mitochondria function as tumor suppressors by supporting differentiated metabolism, while their impairment may push cells toward glycolytic states similar to those seen in stem cells and tumors.