From Mutation to Metabolism: Root Cause Analysis of Cancer’s Initiating Drivers

Background/Objectives: Despite decades of focus on the Somatic Mutation Theory (SMT), survival outcomes for cancer remain modest, with most therapies offering only marginal benefits. Mounting evidence suggests that mitochondrial dysfunction, rather than random mutations, represents the central initiating event in carcinogenesis. Methods: We applied a systems-based Root Cause Analysis (RCA) framework, adapted from engineering and healthcare, to trace modifiable upstream biological drivers of mitochondrial collapse. Literature spanning environmental, nutritional, metabolic, infectious, and hormonal domains was reviewed to identify initiating contributors. Results: We propose a three-layer model of cancer initiation: (1) upstream initiating drivers (toxins, nutrient deficiencies, chronic infections, hormonal disruption, psychosocial stress, and iatrogenic factors); (2) central bioenergetic collapse via mitochondrial dysfunction, oxidative stress, and metabolic instability; and (3) downstream oncogenic phenotype, encompassing genomic instability, inflammation, immune evasion, and tumor progression. RCA organizes these drivers into a coherent sequence, highlighting prevention and intervention leverage points.