Michael J. Hitchler, Frederick E. Domann

Cancer arises from normal cells that acquire a series of molecular changes; however, the founding events that create the clonogens from which a tumor will arise and progress have been the subject of speculation. Through the efforts of several generations of cancer biologists it has been established that the malignant phenotype is an amalgamation of genetic and metabolic alterations. Numerous theories have suggested that either, or both, of these elements might serve as the impetus for cancer formation. Recently, the epigenetic origins of cancer have been suggested as an additional mechanism giving rise to the malignant phenotype. When the discovery that the enzymes responsible for initiating and perpetuating epigenetic events is linked to metabolism by their cofactors, a new paradigm for the origins of cancer can be created. Here, we summarize the foundation of such a paradigm on the origins of cancer, in which metabolic alterations create an epigenetic progenitor that clonally expands to become cancer. We suggest that metabolic alterations disrupt the production and availability of cofactors such as S-adenosylmethionine, α-ketoglutarate, NAD(+), and acetyl-CoA to modify the epigenotype of cells. We further speculate that redox biology can change epigenetic events through oxidation of enzymes and alterations in metabolic cofactors that affect epigenetic events such as DNA methylation. Combined, these metabolic and redox changes serve as the foundation for altering the epigenotype of normal cells and creating the epigenetic progenitor of cancer.