Hereditary cancer syndromes linked to oxidative phosphorylation insufficiency

Abstract Cancer is widely recognized as a genetic disease based on the somatic mutation theory (SMT). This theory posits that cancer is a complex genetic disease arising from inherited or random somatic mutations in proto-oncogenes or tumor suppressor genes, leading to dysregulated cell growth. Hereditary cancer syndromes (HCSs) are genetic conditions with an underlying germline mutation that increases the risk of developing specific cancers. Numerous HCSs have been documented, and it is assumed that the inherited mutations responsible for these syndromes are the primary causes of cancers when they occur, reinforcing the SMT. In contrast, the mitochondrial metabolic theory (MMT) suggests that cancer develops due to a gradual disruption of ATP production through mitochondrial oxidative phosphorylation (OXPHOS). This leads to compensatory ATP production through substrate-level phosphorylation (SLP). Our findings indicate that no inherited mutations are fully penetrant for cancer. Therefore, these inherited mutations should be considered secondary risk factors rather than primary causes of cancer. Furthermore, we found that most, if not all, HCSs impair OXPHOS, induce oxidative stress, and exhibit increased reliance on SLP. Consequently, the heightened risk of cancer associated with HCSs likely stems from mitochondrial respiratory insufficiency and oxidative distress prevalent in these syndromes, thereby supporting the MMT.