September 20, 2002
Researchers Discover New Risk Factor for Colon Cancer
Studies in mice and humans have revealed that carriers of the rare
disease, Bloom syndrome, are at increased risk for developing
colorectal cancer.
In two studies, published in the September 20, 2002, issue of the
journal Science, collaborative teams of scientists present
evidence that a mutation in one of two copies of the Bloom syndrome
gene (BLM) is sufficient to raise the risk of cancer in mice and
humans. The results are the first to show that being a carrier of a
recessive cancer syndrome gene can raise the risk of cancer, even if
that individual does not have the disease itself.
“This is one step toward understanding a complex disease and identifying the combination of factors that may increase risk.”
Joanna Groden
“The findings remind us that knowing your family history of
disease is very important,” said Howard Hughes Medical Institute
investigator Joanna Groden, who led the team that conducted the
experiments in mice. “Even cancers that we think of as common and
age-related can have a hereditary component.”
In the case of Bloom syndrome, people who have two defective copies
of the BLM gene are generally of short stature and have a
variety of physical defects and a predisposition to developing many
types of cancer. Bloom syndrome occurs in all ethnic populations, but
it is more common in Jewish people of European descent (Ashkenazi
Jews).
The BLM protein plays a role in helping ensure that chromosomes are
copied properly during cell division. When the BLM protein is defective
or missing, cells are more likely to acquire or keep DNA-copying errors
that result in mutation. The chromosomes in cells without BLM also may
have trouble getting untangled during cell division, sometimes causing
pieces of chromosomes to break off.
Groden and her colleagues at the University of Cincinnati conducted
a series of experiments in mice that were engineered to carry a single
copy of the mutant Blm gene. These mice, which also had one
normal copy of the gene, made about half the normal amount of BLM
protein.
“Our hypothesis was that if there is less protein present,
cells may be less competent at repairing breaks or carrying out
replication,” said Groden.
To test their idea, the scientists mated the BLM mice with another
type of mouse that is prone to developing intestinal cancer. When they
counted the number of intestinal tumors in the offspring, they found
that mice carrying one Blm gene mutation developed twice as many
tumors as mice without the mutation.
In another experiment, the researchers examined lung cells from the
BLM mice that were cultured in the laboratory. After adding a chemical
that increases the usually low rate of DNA damage during cell division,
they compared DNA damage in normal cells with DNA damage in the BLM
mouse cells. The experiments showed that there were twice as many
fragments of broken chromosomes, counted as micronuclei, in the BLM
mouse cells as there were in normal mouse cells.
“There were subtle increases in the number of
micronuclei,” said Groden. “This suggests that perhaps
there is a reduction in the ability of the helicase to maintain or
repair DNA that accompanies its reduction in amount.”
The results of the mouse study spurred an investigation of the role
of BLM in colon cancer incidence among Ashkenazi Jews, an ethnic group
in which one percent of the population carries the gene mutation that
causes Bloom syndrome. A collaborative team of investigators from
Memorial Sloan-Kettering Cancer Center, the University of Michigan, and
the Technion Faculty of Medicine in Haifa, Israel, studied 1,224
Ashkenazi Jews who developed colon cancer and 1,839 normal controls.
They found that carriers of the Bloom disease gene were nearly three
times as likely to have developed colon cancer.
“This study shows that genes that are relatively common in the
population can change a person’s risk for colorectal
cancer,” said Groden. “This is one step toward
understanding a complex disease and identifying the combination of
factors that may increase risk.”
Groden points out that in a disease like colon cancer, knowing risk
factors is especially important because screening is available that can
catch the disease early and greatly increase the chances of a cure.
According to the American Cancer Society, there will be 148,300 new
cases of colon cancer in the United States in 2002, and 56,600 deaths,
making colon cancer the third most common cancer for both men and
women.
“This is the kind of study that shows the power of using the
mouse as a model for human disease,” said Groden. “It is
always the hope of those of us in the mouse modeling community to study
genes that will improve how we treat diagnose and counsel people. If
these discoveries encourage even a few people in the Ashkenazi Jewish
population to learn their family history and go for early colon cancer
screening then that’s terrific.”
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