TAMPA, FlaOver the last 5 years, researchers have identified
two major types of genetic instability that occur relatively early in
cancer development, Mark Redston, MD, of Mount Sinai Hospital,
Toronto, said at the American Cancer Societys 42nd
Annual Science Writers Seminar.
The more common of these genetic instabilities is chromosomal
instability, which is present in about 85% of cancers and is
characterized by gross alterations in the chromosomal structure. The
second form, microsatellite instability, is present in about 15% of
cancers and features subtle DNA mutations, particularly in the
regions of repetitive sequences known as microsatellites.
The exact cause of chromosomal instability remains mostly unknown,
Dr. Redston said, but microsatellite instability is known to stem
from a failure of the normal DNA mismatch repair process. In
cancers with microsatellite instability, one of the normal DNA
mismatch repair proteins is turned off by a mutation, resulting in
failure to correct spontaneous DNA mutations, he said.
In 80% to 90% of colorectal cancers with microsatellite instability,
the mismatch repair gene abnormality is present only in tumor cells.
In approximately 10% to 20%, however, the mismatch gene defect is
associated with hereditary non-polyposis colorectal cancer (HNPCC)
and is present in both tumor cells and normal cells.
Dr. Redston and his colleagues Drs. Steven Gallinger and Robert Gryfe
were the lead investigators in a study of 607 colorectal cancer
patients in southern Ontario to determine if microsatellite
instability is associated with distinct clinical behavior of tumors.
All of the cancers were tested for microsatellite instability using
polymerase chain reaction (PCR). Then clinical features and survival
were compared between the tumors with and without microsatellite
High-frequency microsatellite instability was found in 17% of the
colorectal cancers, Dr. Redston said. In a multivariate analysis,
microsatellite instability was associated with a significantly
increased survival rate. About 50% of patients with
microsatellite-stable cancers were dead after 10 years, compared with
about 25% of those whose cancers had microsatellite instability,
Furthermore, regardless of the tumors size or depth of
invasion, cancers with microsatellite instability were less likely to
metastasize to distant sites. Interestingly, he said,
pathologic findings revealed that microsatellite instability
tended to confer a predisposition to poorly differentiated,
These recently published findings (N Engl J Med 342:69-77,
2000) suggest that the absence or presence of microsatellite
instability may represent two distinct diseases. This
hypothesis is strongly supported by differences in the underlying
genetic mechanisms of cancer formation, Dr. Redston said.
He predicts that in the near future, microsatellite instability will
become a standard test for classifying colorectal cancers, but added
that more studies are required to determine how this could help
oncologists tailor therapy for patients.
We dont fully understand why microsatellite instability
is associated with improved survival; however, it is possible that
the severity of the genomic instability renders these cells more
susceptible to apoptosis, he speculated. It has also been
noticed that these cancers are associated with an intense
inflammatory response, he said, suggesting that the immune
system is better able to stop them from metastasizing.
Continued research into this area should give oncologists new and
revealing insights about cancer cell behavior, Dr. Redston concluded.