October 24, 2005
Blood Test Shows Promise in Early Identification of Colon Cancer
Researchers have developed a blood test that detects the presence of
fragments of mutated genes that are present in colon cancer cells.
Their pilot studies provide the basis for diagnostic assays for cancer
that could allow physicians to detect tumors at an early stage.
The research team, led by Howard Hughes Medical Institute
investigator Bert Vogelstein at The Sidney Kimmel Cancer Center at the
Johns Hopkins Medical Institutions, published its findings on October
24, 2005, in the online Early Edition of the Proceedings of the
National Academy of Sciences (PNAS). Vogelstein and his colleagues
at Hopkins collaborated on the studies with researchers from Israelitic
Hospital in Germany.
“Assuming that future larger studies support these initial results, our hope is that such a test could be used to detect early tumors.”
Bert Vogelstein
“Each type of test for cancer has advantages and
disadvantages,” said Vogelstein. “One of the primary
advantages of testing for mutations — compared with a test for PSA in
the serum or blood in the feces, for example — is that mutations are
not simply associated with the development of neoplasia. They are the
causes of neoplasia.” Indirect tests such as PSA or the fecal
occult blood test can yield a positive result in the absence of cancer,
he said, “so, at least in principle a much higher degree of
specificity is possible when one is looking for mutations in genes that
underlie a cancer.”
The blood test is based on a technique called BEAMing, a name
derived from the principal components used in the technique - metal
beads, emulsion, amplification of DNA and magnetics. BEAMing involves
attaching DNA fragments of a cancer gene from blood to metal beads and
amplifying the number of copies of those fragments to a detectable
level by using the polymerase chain reaction technique. The beads, with
the DNA fragments tagged to denote whether they are normal or aberrant,
can then be manipulated using magnetism and separated for measurement
using a technique called flow cytometry.
The researchers tested BEAMing on blood samples drawn from colon
cancer patients. They found that fragments of the cancer-causing gene,
adenomatous polyposis coli (APC), were detectable in the
blood samples. According to Vogelstein, the studies suggest that DNA
fragments from tumors are released into the blood when immune system
scavenger cells called macrophages destroy dead tumor cells.
Using a refined version of the BEAMing technique with improved
sensitivity and specificity, the researchers tested whether they could
reliably detect mutant forms of APC in blood drawn from 22
patients with colon cancer. They found they could easily identify
mutant DNA in patients with advanced disease.
“When we analyzed the blood of patients with earlier stage
cancers that were presumably curable by surgery, we could still find
mutant DNA fragments,” said Vogelstein. “They were a
smaller fraction of the DNA fragments compared with patients with more
advanced cancers, but they were still detectable in more than sixty
percent of the patients.” By contrast, blood from patients with
benign colon tumors showed little evidence of mutant DNA fragments.
“While tests such as colonoscopy can detect more than
eighty-five percent of colorectal tumors, including large premalignant
ones, blood tests could prove useful for the large number of patients
who don't undergo colonoscopy,” said Vogelstein. “Patient
compliance should be very high, because most patients routinely have
blood drawn when they visit their physician. And such tests should have
high specificity because they detect mutations that are only present in
cancer cells.”
While the test may one day be applied to diagnose a wider variety of
cancers, those potential applications will depend on whether
researchers can identify additional genetic mutations that are highly
specific for each type of cancer, said Vogelstein. “In colon
cancers, the mutations are well known, which sets the stage perfectly
for this kind of test,” he said. “Similar tests should be
possible for cancers of the stomach, ovary and pancreas. However, in
other cancer types, such as those of the breast, only a relatively
small number of mutations have been identified. So the broadness of
this approach will to some extent depend on the discovery of more of
the mutations responsible for other forms of tumorigenesis.”
The test could fill an important gap in the methods available for
the early diagnosis of cancers. “For many cancers, such as those
of the pancreas, stomach, lung and bladder, there really aren't any
screening tests available,” said Vogelstein. “Assuming that
future larger studies support these initial results, our hope is that
such a test could be used to detect early tumors. And if the tests
could detect even a third of patients with cancers who were
pre-symptomatic and curable by surgery, that would represent an
extremely useful advance.”
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Jennifer Michalowski
