Gazette
masthead
   About The Gazette Search Back Issues Contact Us    
The newspaper of The Johns Hopkins University January 9, 2006 | Vol. 35 No. 16
 
New View of Cancer: 'Epigenetic' Changes Come First

Traditional view may have to give way to complicated one, scientists suggest

By Joanna Downer
Johns Hopkins Medicine

A Johns Hopkins researcher, with colleagues in Sweden and at the Fred Hutchinson Cancer Research Center, suggests that the traditional view of cancer as a group of diseases with markedly different biological properties arising from a series of alterations within a cell's nuclear DNA may have to give way to a more complicated view. In the January issue of Nature Reviews Genetics, online Dec. 21, he and his colleagues suggest that cancers instead begin with "epigenetic" alterations to stem cells.

"We're not contradicting the view that genetic changes occur in the development of cancers, but there also are epigenetic changes, and those come first," said lead author Andrew Feinberg, King Fahd Professor of Medicine and director of the Center for Epigenetics in Common Human Disease at Johns Hopkins.

Cells affected by epigenetic changes look normal under a microscope at low levels of resolution, Feinberg said, "but if you look carefully at the genome, you find there are subtle changes." By tracking these changes, he suggests, doctors potentially could treat people before tumors develop in much the same way as cardiologists prescribe cholesterol-lowering drugs to help prevent heart disease.

Epigenetic changes — those that don't affect the gene's sequence of DNA but change the gene in other ways — influence a wide variety of human diseases, including cancer, birth defects and psychiatric conditions. Epigenetic alterations include the turning off or quieting of genes that normally suppress cancer and the turning on of oncogenes to produce proteins that set off malignant behavior.

Epigenetic changes are found in normal cells of patients with cancer and are associated with cancer risk, Feinberg noted.

As one example, in a study published in the Feb. 24, 2005, online version of Science, Feinberg and colleagues in the United States, Sweden and Japan reported that mice engineered to have a double dose of insulinlike growth factor 2 had more primitive precursor cells in the lining of the colon than normal mice. When these mice also carried a colon cancer-causing genetic mutation, they developed twice as many tumors as mice with normal IGF2 levels. The extra IGF2 stemmed not from a genetic problem, or mutation, but from an epigenetic problem that improperly turned on the copy of the IGF2 gene that should have remained off.

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 noted. 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 said.

Authors on the review, in addition to Feinberg, are Rolf Ohlsson, of Uppsala University, Sweden; and Steven Henikoff, of the Howard Hughes Medical Institute at the Fred Hutchinson Cancer Research Center.

GO TO JANUARY 9, 2006 TABLE OF CONTENTS.
GO TO THE GAZETTE FRONT PAGE.


The Gazette | The Johns Hopkins University | Suite 540 | 901 S. Bond St. | Baltimore, MD 21231 | 443-287-9900 | gazette@jhu.edu