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