In this 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 viewing these genes primarily as drivers of cancer through mutation, they present them as fundamentally involved in 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—their discussion suggests that disruptions in mitochondrial metabolism may precede and potentially drive many of the genetic alterations commonly associated with cancer. They also highlight evidence from exercise physiology studies showing that genes such as BRCA1 and p53 play key roles in maintaining mitochondrial performance and genomic stability during energetic stress, reinforcing the idea that these genes serve important metabolic functions under normal conditions.

Bob and Pete further critique how the naming and study of cancer genes has biased research toward mutated functions, leaving their normal physiological roles underexplored. They connect this perspective to broader frameworks such as the atavistic theory of cancer, which proposes that cancer represents a reversion to primitive metabolic programs characterized by fermentation and substrate-level phosphorylation. In this view, mitochondria act as functional tumor suppressors by sustaining differentiated cellular metabolism, and when mitochondrial capacity declines, cells compensate by shifting toward glycolytic states similar to those seen in stem cells and tumors. The discussion also touches on environmental factors—including tobacco, diet, and infections—which account for the majority of cancers, yet cancer research remains heavily centered on genetic mutation models, reflecting longstanding scientific dogma and institutional inertia that have hindered exploration of cancer’s metabolic origins.

Featured paper:

• Hereditary cancer syndromes linked to oxidative phosphorylation insufficiency: Kaplan et al (2025).
• Metabolic Signatures of Performance in Elite World Tour Professional Male Cyclists: Nemkov et al (2023).
• Skeletal Muscle Function Is Dependent Upon BRCA1 to Maintain Genomic Stability: Tarpey et al (2021).
• p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content: Park et al (2009).

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