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Combination of three blood proteins may form basis for a biomarker screen for ovarian cancer

A new test measuring blood levels of three proteins suggests there may be a molecular signature specific to ovarian cancer that can be used to diagnose cases at an earlier stage, according to an article in the August 15th issue of Cancer research.

The current laboratory testing, which used blood samples from patients in the US and international hospitals, identified three proteins as a truncated form of transthyretin, a fragment of ITIH4, and apolipoprotein A1.

"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, PhD, a coauthor of the article. "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."

The researchers emphasized 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 noted, 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."

The authors believe, however, that with some refinements it may already have use for helping determine whether a pelvic mass is ovarian cancer.

In a systematic search to find the most promising blood proteins for their test, the 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 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.

"Typically, only half of early-stage ovarian cancer patients have high blood levels of a standard marker called CA125," said Zhen Zhang, PhD, lead author of the study, “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) 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) compared with 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 patients with ovarian, breast, colon, or prostate cancer and healthy people. Protein markers from the 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 are 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.


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