Researchers at Johns Hopkins and Ohio State
universities have found that the number of
copies of a particular gene can affect the severity of
colon cancer in a mouse model. Publishing in the
Jan. 3 issue of Nature, the research team describes
how trisomy 21, or Down syndrome in humans, can
repress tumor growth.
"We took a new approach to a 50-year-old debate about
whether people with Down syndrome
develop cancer less often than other people," said Roger H.
Reeves, professor of physiology in the
McKusick-Nathans Institute of Genetic Medicine at Johns
Hopkins. "Studying the genetic differences
associated with Down syndrome has revealed a new way of
thinking about repressing cancer growth in
The research team started with a mouse model that
carries, rather than a whole extra copy of
chromosome 21, as is seen in trisomy 21 (or Down syndrome),
a partial copy containing 108 genes. They
then mated those trisomic mice to mice that carry a
mutation that causes intestinal tumors, similar to
those seen in colon cancer in humans. The trisomic, colon
cancer mice had 44 percent fewer intestinal
tumors compared to the colon cancer mice without the extra
The team then used another mouse model of Down
syndrome, one that carries extra copies of
only 33 of the genes on chromosome 21, and repeated their
genetic crosses. Mice with three copies of
the 33 genes developed half the number of tumors as mice
with the standard two copies. Mice
carrying a deletion that left them with only one copy of
these 33 genes developed twice the number of
tumors as usual.
"Not only does having an extra copy of one or more of
these genes repress tumor formation, it
turns out that missing a copy enhances tumor growth. This
was really surprising," Reeves said.
Taking a closer look at the 33 genes to identify a
likely culprit for the dose-specific
relationship with tumor growth, the researchers focused on
one gene, Ets2, which previously has been
implicated as a cause of cancer. However, some research
suggested that Ets2 activity might be
involved in pathways that cause cells to die.
They then repeated their genetic crosses, this time
with mice that had three, two or one copy
of the Ets2 gene only. Once again, mice that were trisomic
for 33 genes (including Ets2) had fewer
tumors, but mice that were trisomic for 32 of these genes
but had the normal two copies of Ets2 had
a tumor number similar to control (nontrisomic) mice. Mice
with just one copy of Ets2 developed more
"These results support studies concluding that people
with Down syndrome get fewer cancers of
many types. While we've only shown this effect with Ets2
and a particular type of colon tumor in mice,
we think that the human Ets2 gene might contribute to
resistance toward other types of cancer,
based on what happens in Down syndrome," Reeves said.
Michael Ostrowski, an Ohio State cancer researcher and
Ets2 expert who developed the mouse
models used in this study, said, "Our findings are
significant because they broaden the definition of an
'oncogene' or 'tumor suppressor gene' to include the effect
of gene dosage. They also suggest that
finding ways to increase the expression of genes such as
Ets2 might lead to a new strategy for
treating or controlling cancer."
The research was funded by the National Institute of
Child Health and Development and the
National Cancer Institute.
Authors on the paper are Fu Li and Ostrowski, both of
Ohio State; and Thomas Sussan, Annan
Yang and Reeves, all of Johns Hopkins.