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Smoking
related to subset of Colorectal Cancers with
absent DNA Repair Proteins
Newswise — Smoking puts
older women at significant risk for loss of
DNA repair proteins that are critical for
defending against development of some
colorectal cancers, according to research
from a team led by Mayo Clinic scientists.
In a study being
presented at the annual meeting of the
American Association for Cancer Research (AACR),
the researchers found that women who smoked
were at increased risk for developing
colorectal tumors that lacked some or all of
four proteins, known as DNA mismatch repair
(MMR) proteins.
These proteins keep
cells lining the colon and rectum healthy
because they recognize and repair genetic
damage as well as mistakes that occur during
cell division.
Researchers believe
that, in this study population, few if any
of the four proteins were absent because of
an inherited genetic alteration.
“We think that smoking
induces a condition within intestinal cells
that does not allow MMR genes to express
their associated proteins, and this loss
leads to formation of tumors in some women,”
says the study’s lead author, Mayo
gastroenterologist Paul Limburg, M.D.
The researchers also
discovered a direct association between the
number of cigarettes smoked daily by study
participants and increased risk of
developing these specific tumors.
They say many previous
studies have found only a very weak positive
association between use of cigarettes and
development of the cancer.
“Our findings suggest
that tumors may form because cells can’t
repair themselves from damage induced by
smoking,” Dr. Limburg says.
“Tobacco toxins appear
to block the DNA repair genes from producing
their beneficial proteins.
“We are beginning to
realize that there might be different risk
factors for different subsets of colon and
rectal cancers.
"Smoking
is emerging as a potentially important,
modifiable risk factor among postmenopausal
women,” he says.
The findings also could
have other clinical implications with
respect to chemotherapy, as tumors that lack
MMR proteins might respond differently to
standard treatment regimens, Dr. Limburg
says.
The research team
examined data from the 41,836-participant
Iowa Women’s Health Study and selected those
1,421 women who developed colorectal cancer
since the study began in 1986.
They then worked with
the Iowa Cancer Registry and pathology
laboratories around the state to collect
tumor specimens from these patients.
To date, they have
retrieved about 50 percent of the samples.
This study, a first analysis, includes 432
samples, or about 30 percent of the group.
They analyzed the
tumors for presence of four DNA mismatch
repair proteins known to be active in cells
lining the colon and rectum.
Samples that had
all four were labeled MMR-positive. Tumors
with less than four were tagged as MMR-negative.
The researchers then
correlated information reported by the
patients on whether they had ever smoked and
how many cigarettes they used daily with MMR
protein patterns in their tumors.
They found that smoking
status was not significantly associated with
development of colorectal cancer in the 432
patients in general.
However, when the
scientists examined colorectal cancers in
women smokers with the perspective of MMR-deficient
gene involvement, there was a strong
association between smoking and MMR-negative
status.
For example, former
smokers had a 61 percent increase in
relative risk for MMR-negative colorectal
cancer compared to never smokers, and
“current” smokers were more than twice as
likely to develop colorectal tumors with
absent mismatch repair proteins.
The association between
smoking and MMR-negative colorectal cancer
also steadily increased with the number of
cigarettes a woman smoked per day, Dr.
Limburg says.
The relative risk for
MMR-negative cancer increased 54 percent if
a patient smoked 1–19 cigarettes daily, more
than twofold for 20 cigarettes a day, and
more than threefold for a woman who smoked
more than 30 cigarettes daily.
He adds that the link
between smoking with loss of MMR proteins
and development of colorectal cancer may
also occur in male smokers and in younger
people, but that the researchers can’t make
such associations because this study used
data only from older women.
Other Mayo Clinic
researchers included Robert Vierkant; Amy
French; Alice Wang; Susan Slager, Ph.D.;
Thomas Smyrk, M.D.; Stephen Thibodeau,
Ph.D.; and James Cerhan, M.D., Ph.D.
Collaborators from other institutions
included Lisa Harnack, Ph.D., and Kristin
Anderson, Ph.D., M.P.H., University of
Minnesota Cancer Center, Minneapolis; John
Potter, M.D., Ph.D., Fred Hutchinson Cancer
Research Center, Seattle; and Charles Lynch,
M.D., Ph.D., University of Iowa College of
Public Health, Iowa City.
The study, which is
ongoing, is funded by the National Cancer
Institute.
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