Feinberg and his colleagues propose that cancers develop via a three-step process. First, there is an epigenetic disruption of progenitor cells within an organ or tissue, altered by abnormal regulation of tumor-progenitor genes. This leads to a population of cells ready to cause new growth.
The second step involves an initiating mutation within the population of epigenetically disrupted progenitor cells at the earliest stages of new cell growth, such as the rearrangement of chromosomes in the development of leukemia. This mutation normally has been considered the first step in cancer development.
The third step is genetic and epigenetic instability, which leads to increased tumor evolution.
Many of the properties of advanced tumors, including the ability to spread, or metastasize, are inherent properties of the progenitor cells that give rise to the primary tumor, Feinberg notes. These properties do not necessarily require other mutations to occur.
"Greater attention should be paid to the apparently normal cells of patients with cancer or those at risk for cancer, as they might be crucial targets for epigenetic alteration and might be an important target for prevention and screening," he says.
Authors on the review are Andrew Feinberg of Johns Hopkins; Rolf Ohlsson of Uppsala University, Sweden; and Steven Henikoff of the Howard Hughes Medical Institute at the Fred Hutchinson Cancer Research Center.