Johns Hopkins
Kimmel
Cancer Center researchers have designed a blood test to
detect ovarian cancer using three proteins found in common
in the blood of women with the disease. Their preliminary
studies with the new test suggest a molecular signature
exclusive to this deadly cancer, known for its ability to
remain undetected and spread quickly.
The test, described in the Aug. 15 issue of Cancer
Research, identifies the proteins as a truncated form
of transthyretin, a fragment of ITIH4 and apolipoprotein
A1, teased out with a rigorous evaluation of protein
patterns present in blood samples from ovarian cancer
patients at several U.S. and international hospitals. Other
research groups are evaluating ovarian cancer blood tests
that use protein profiles consisting of tens of thousands
of unidentified molecules.
"By identifying a select group of biomarkers specific
to ovarian cancer, we not only know the proteins we are
dealing with, but we can trace them back to alterations in
the genetic code of ovarian cancer cells," said Daniel W.
Chan, professor of
pathology and director of the Biomarker Discovery
Center at Johns Hopkins. "We are focusing on the markers
for which we have good biological reasoning behind their
selection and hope to expand the panel of markers to catch
as many variations in ovarian cancer proteins as
possible."
Chan and his co-workers emphasize that the test will
not be commercially available for screening the population
at large until completion of further validation studies in
larger groups of patients. And even then, Chan said, it is
never going to be possible for a blood test to correctly
diagnose 100 percent of cancerous tumors 100 percent of the
time.
"The goal is to come as close as possible to that by
using this test in combination with other available
diagnostic tools," he said. The researchers believe,
however, that with some refinements the test already may
have use in helping to determine whether a pelvic mass is
ovarian cancer.
In a systematic search to find the most promising
blood proteins for their test, the Johns Hopkins scientists
conducted a multicenter study and screened a total of 195
blood samples from two groups of ovarian cancer patients,
healthy people and patients with benign ovarian tumors. A
sophisticated bioinformatics program was used to select
proteins present at unusually high or low levels in ovarian
cancer samples as compared with normal or benign. Samples
in the two groups were analyzed separately to account for
differences in patient populations and sample collection
techniques. Then, researchers compared protein profile
results in these two groups and ultimately narrowed the
search for potential marker candidates to the three
proteins, one of which (ITIH4) is commonly found at high
levels in ovarian cancer and the other two at lower
levels.
According to Zhen Zhang, associate professor of
pathology and associate director of the Biomarker Discovery
Center, "Typically, only half of early-stage ovarian cancer
patients have elevated blood levels of a standard marker
called CA125. But combining CA125 with our new markers may
improve early detection capabilities."
The new proteins were screened against a separate
collection of blood samples from patients with normal and
cancerous tissues. Of 23 patients with early-stage ovarian
cancer, the three protein markers plus CA125 correctly
identified cancer 74 percent of the time (17 of 23) as
compared to 65 percent (15 of 23) with CA125 alone.
Although the sample size was too small for this difference
to be statistically significant, the scientists conducted
further studies lowering the cutoff value for CA125 to
below current standards. The new test plus CA125 as well as
CA125 alone detected 83 percent (19 of 23) of the cancers.
In addition, the new test plus CA125 correctly identified
healthy samples 94 percent of the time (59 of 63) as
compared to 52 percent (33 of 63) for CA125 alone.
To verify that the candidate markers were specific to
ovarian cancer, the scientists also compared results of the
protein profiles with a separate group of blood samples
from 142 Johns Hopkins ovarian, breast, colon and prostate
cancer patients and healthy people. Protein markers from
Hopkins' ovarian cancer samples matched those from the
other two groups of blood samples. Breast, colon and
prostate cancer samples exhibited levels of the three
proteins closer to those of normal patients, indicating
that the markers may be exclusive to ovarian cancer.
The scientists will conduct further studies to map all
three proteins to the genetic pathways linked to ovarian
cancer development and combine the blood test with
radiologic tools such as ultrasound. They also will search
for more proteins to add to the current panel of
markers.
This research was funded by the National Cancer
Institute and Ciphergen Biosystems, which has licensed the
test.
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