The wayward methyl group and the cascade to cancer

Abstract

We propose here a hypothesis of the cause of cancer that brings together fundamental changes in methyl-group metabolism resulting in methionine dependence and global DNA hypomethylation which destabilizes the genome leading to aneuploid karyotypes which evolve and stabilize into autonomous cancer. Experimental support for this hypothesis is that methioine dependence is a general metabolic defect in caner. Methionine dependence is due to excess use of methionene for aberrant transmethylation reactions that apparently divert methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomena in cancer. Global hypomethylation leads to an unstable genomes and aneuploid karyotypes, another general phenomena in cancer. The excessive and aberrant use of methionine in cancer is strongly observed in [11C]methionine PET imaging, where high uptake of [11C]methionine results in a very strong and selective tumor signal compared with normal tissue background. [11C]methionine is superior to [18C] fluorodeoxyglucose (FDG)-PET for PET imaging, suggesting methionine dependence is more tumor-specific than glucose dependence.