Epigenetic theories of cancer initiation.

I argue that carcinogenic insults injure many cells rather than mutate a few. This results from evidence that such insults convert too many cells to a precancerous state and that too many of the converted cells then revert to plausibly involve mutation and its repair; from evidence that the delays between such insults and chemically demonstrable mutations are long enough to easily allow nonmutational mechanisms to work; from evidence that even ionizing radiation first acts on the cytoplasm and mainly affects cells unhit by it; from the fact that such insults induce proto-oncogene expression far too quickly to do so by mutation; and from the fact that fusions of various cells and cell parts show that the tumorous or nontumorous nature of the product depends on its cytoplasmic rather than its nuclear component. I further argue that reduced DNA methylation, modifications of the histone code, and tissue disorganization are the three main mechanisms of epigenetic cancer initiation. Hypomethylation would result from DNA excision repair. Moreover, a methyl-deficient diet is carcinogenic and demethylation is also known to be carcinogenic via the histone code. Finally, I strongly argue for tissue disorganization as a mechanism of cancer initiation. This results from evidence that skin carcinogens disrupt the dermal/epidermal connection and from the fact that tumorigens swiftly disrupt gap junctions, as well as from evidence that such disruption is tumorigenic.