Researchers Discover Protein Signatures for Prostate Cancer That Could Improve Diagnosis of Early Disease
A new study shows that testing blood samples for antibodies that target prostate cancer cells may help identify patients with early stages of the disease. In the September 22, 2005, issue of New England Journal of Medicine*, researchers report the findings may lead to a new test that could complement the prostate specific antigen (PSA) test in detecting early stage prostate cancer. The study was supported by the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI), part of the National Institutes of Health.
Previous studies have found that men with normal blood levels of PSA (4.0 ng/ml or less) can have prostate cancer**. Furthermore, PSA-based prostate cancer screening has a high rate of false-positive results (up to 80 percent). Therefore, scientists have been looking for additional ways to adequately screen for early disease.
"Using PSA testing alone results in millions of dollars being spent on prostate biopsies due to false-positive results. We don't yet know if our new findings will save lives, but there could be a major cost saving by decreasing the number of prostate biopsies performed every year," said Sudhir Srivastava, Ph.D., chief, Cancer Biomarkers Research Program and director for the EDRN.
The panel of 22 target proteins identified in this study showed an 88.2 percent specificity value for prostate cancer, which indicates the proportion of those tested who did not have cancer and were correctly identified as being free of disease. The test also showed an 81.6 percent sensitivity value, indicating the proportion of those patients with cancer that were correctly diagnosed as having prostate cancer.
Scientists know that cancer patients produce antibodies to proteins, called antigens, which are present on the surface of tumor cells. Antibodies themselves are proteins produced by immune cells to help fight and destroy viruses, bacteria, and other foreign substances that invade the body. As a cancer cell grows, normal antigens can be presented on a cell surface in a different way. The body then recognizes these antigens as foreign and produces antibodies to these cells. These particular antibodies are termed autoantibodies, because they react to a substance produced by the body itself.
"In this study, we took advantage of the body's own immune system as a detector of prostate cancer," said Arul Chinnaiyan, M.D., Ph.D., study leader, University of Michigan Medical School, Ann Arbor. "While the present study focused on the detection of prostate cancer, this general approach has potential to be developed for other cancers, as well as for other human diseases that in some way perturb the immune system."
The use of autoantibody signatures may be more useful in combination with PSA testing in reducing the number of false-negative and false-positive tests obtained than when using PSA testing alone. Statistical analysis of these results shows that the protein panel performed better in distinguishing between prostate cancer patients and controls than the PSA test. The panel of 22 proteins predicted the presence of cancer accurately 92.7 percent of the time, while PSA predicted the presence of cancer only 79.6 percent of the time. The use of autoantibody signatures may be most informative in assessing the need for a biopsy in patients with PSA values of 10ng/ml or less.
"Identification of autoantibodies is an exciting area of research. We are also looking to see if the autoantibodies produced against prostate cancer cells are specific only to this disease," said Srivastava. "Knowledge of whether antibodies are specific to particular organs will be important when considering a design for any new test."
A total of 257 blood samples were tested for novel prostate cancer autoantibodies; blood samples from 119 patients with prostate cancer were studied prior to surgery and 138 samples were from patients without prostate cancer. Among the 22 peptides found, the genes that code four of them were identified: eIF4G1, BRD2, RPL13a, and RPL22***.
Collaborators supported by the EDRN will further analyze the peptide panel test. Both the reproducibility of this study protocol and new blood samples will be used to validate the peptide panel. For clinical application to occur, the test will need to be validated in different populations and at various EDRN testing sites, a process that is being planned.
For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* Wang X, Yu J, Sreekumar A, Varambally S, Shen R, Giacherio D, Mehra R, Montie JE, Pienta KJ, Sanda MG, Mantoff PW, Rubin MA, Wei JT, Ghosh D, Chinnaiyan AM. Autoantibody Signatures in Prostate Cancer. New England Journal of Medicine, September 22, 2005: 353 (12): 16-27.
** Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA. Prevalence of Prostate Cancer among Men with a Prostate-Specific Antigen Level Less Than or Equal to 4.0 ng per Milliliter. New England Journal of Medicine, May 27, 2004; 350 (22): 2239-2246.
*** eIF4G1 (eukaryotic translation initiation factor 4 gamma 1), BRD2 (bromodomain containing 2), RPL13a (ribosomal protein L13a), and RPL22 (ribosomal protein L22).