Microsatellite instability as a marker
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One of the most promising molecular markers in colorectal
cancer, called microsatellite instability (MSI), was first discovered
as the basis of hereditary nonpolyposis colorectal cancer and later
found in a sizable minority of sporadic colorectal cancers as well.
MSI refers to increases or decreases in the length of repeating
mono- or dinucleotides, such as (CACACA)n, located mostly in intronic
DNA. MSI is due to mutations in genes that correct DNA mismatches
occurring during replication. "This is equivalent to turning off
normal DNA repair," says Mark Redston, MD, staff pathologist at
Mt. Sinai Hospital, Toronto. In colon cancer, MSI is due predominantly
to inactivation of one of two major mismatch repair (MMR) genes,
hMSH2 or hMLH1. (The "h" stands for "human"; these genes are homologues
of MMR genes originally found in E. coli.)
Dr. Redston and his colleagues reported early this year (N Engl
J Med. 2000;342:69-77) in a population-based series of colorectal
cancer patients 50 years of age or younger at diagnosis that the
presence of MSI was associated with a significant survival advantage
independent of tumor stage and other standard prognostic factors.
Dr. Redston’s group and others have shown that hMSH2 and hMLH1 deficiency
can be as reliably identified by immunohistochemistry for the involved
proteins in colon cancer cells as by direct analysis of the genes.
"The two are almost synonymous," Dr. Redston told CAP TODAY, especially
in cases with high-frequency MSI-where two of the five repeat regions
of DNA tested show MSI. He notes that the 17 percent incidence of
MSI in their cohort might be a bit high, since these patients were
younger, but that 15 percent is a truly representative figure.
It is not surprising to find a difference in survival between patients
whose tumors have the MMR defect and those without it, since the
two types of colorectal cancer are biologically distinct in other
ways as well. Specific tumor suppressor genes, such as transforming
growth factor beta-2 receptor, are mutated only in MMR-deficient
colorectal cancers. And, Dr. Redston notes, "Many colon cancers
with MSI are T4M0-they are very large and invade locally, but don’t
metastasize. That is very unusual. So there is something different
about their biology." MSI-positive colorectal cancers show a prominent
host immune response and are often surrounded by a band of lymphocytes
and tumor infiltrating lymphocytes. "There is something very important
to be learned about the immune response to tumors in the setting
of microsatellite instability," Dr. Redston says.
Because of these biological differences, Dr. Redston and others
believe that tumors with MSI and those without it will respond to
treatments differently. "It has yet to be shown that microsatellite
instability can be used as a predictive marker in planning treatment
strategy," Dr. Redston acknowledges. But, he says, most large multicenter
oncology trials in North America now are starting to build MSI into
the study design as a variable to differentiate treatment responses.
And some groups are looking retrospectively at paraffin blocks from
studies in the 1980s that showed 5-fluorouracil to be superior to
placebo to see if microsatellite instability correlated with response.
"It is our hope and belief," Dr. Redston says, "that studies in
the next couple of years, given the biological differences between
tumors with microsatellite instability and those without, should
show this to be one of the most powerful markers for separating
two distinct types of tumors."
Colorectal cancers with the MMR phenotype have other clinical implications,
according to Jurgen Stahl, MD, senior lecturer in anatomic pathology
at Flinders University School of Medicine, Adelaide, Australia,
who wrote a commentary on this topic. (Advances in Anatomic Pathology.
2000;7:85-93) "Even in populations with sporadic colorectal cancer,
these mutations can occur and have very important clinical implications,"
Dr. Stahl told CAP TODAY. "People who have those genetic abnormalities
have a higher chance of developing a second colorectal carcinoma
in the near future and can develop other cancers as well. In women
we see particularly endometrial and ovarian adenocarcinoma."
Detection of the MMR defect in patients with colorectal cancer
identifies those who need further screening, whereas individuals
with typical colorectal cancer would be able to stop screening a
few years after surgery, Dr. Stahl notes. Although some authors
have recommended screening for MMR in all persons with colorectal
cancer, Dr. Stahl comments, "I’m not really sure how practical that
is from a cost and work point of view. I would screen colorectal
cancers in people under age 50 and those that had developed on the
right side, in the ascending colon."
-William Check, PhD