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Combined Biomarkers Improve Accuracy of Prostate Cancer Detection

By Robin Arnette
August 2009

Shuk-mei Ho, Ph.D.
Ho, above, has also studied the epigenetic alterations ( involved in the development of prostate cancer. (Photo courtesy of Shuk-mei Ho and the University of Cincinnati Medical Center)

Bin Ouyang, Ph.D.
First author Bin Ouyang, Ph.D., is a research associate with the Department of Environmental Health, University of Cincinnati Medical Center. (Photo courtesy of Shuk-mei Ho and the University of Cincinnati Medical Center)

According to data from 2004-2006, the National Cancer Institute ( Exit NIEHS estimates that one in six American men will be diagnosed with prostate cancer during their lifetime. Since early detection of the disease increases the likelihood of survival, physicians routinely use serum prostate specific antigen (PSA) screening and subsequent tissue biopsy to determine whether a patient has prostate cancer. However, recent findings ( Exit NIEHS from a team led by NIEHS grantee Shuk-mei Ho, Ph.D., suggest that a dual marker test comprised of a-methylacyl-CoA racemase (AMACR) and prostate cancer antigen 3 (PCA3) provides increased sensitivity and accuracy compared to PSA testing alone.

These promising results appeared in the June 2009 edition of The Journal of Urology. This study was the first to examine the applicability of the combined biomarkers in the detection of prostate cancer in urine.

Ho ( NIEHS, chair of the Department of Environmental Health at the University of Cincinnati Medical Center, knew that a percentage of men with elevated PSA levels in their blood - a key indicator of prostate cancer - also have negative biopsy results. Her goal was to develop a sensitive test that would prevent these patients from having to undergo repeated biopsies. "Not only will this assay save billions of dollars in unnecessary biopsies each year, but it will be particularly useful for men over 70 years old who have high PSA numbers, but negative biopsies," Ho said. "Because of their advanced age, do we really want to subject them to continuous biopsies?"

AMACR regulates peroxisomal beta-oxidation of phytol-derived branch chain fatty acids and PCA3 is a noncoding mRNA that is only expressed in the kidney and prostate epithelial cells. Previous studies from other laboratories determined that these and several other proteins were found in urine samples of patients with prostate cancer, and therefore had great potential as diagnostic markers for the disease.

For the study of the combined AMACR-PCA3 assay, 92 patients, 43 with prostate cancer and 49 without, were recruited from the urological clinic at the University of Cincinnati Medical Center. The patients gave urine samples after digital examination, but before receiving an ultrasound-guided prostate biopsy. Ho's team isolated RNA, used reverse transcriptase to convert to cDNA and then subjected the samples to quantitative real time polymerase chain reaction (qRT-PCR). Ho used several statistical analysis tools to resolve the sensitivity and specificity of AMACR and PCA3 scores in urine.

AMACR alone had 70 percent sensitivity and 71 percent specificity, while PCA3 alone had 72 percent sensitivity and 59 percent specificity. However, using the two together increased the sensitivity to 81 percent and the specificity to 84 percent. In contrast, serum PSA readings indicated 77 percent sensitivity and 45 percent specificity. Because the urinary AMACR- PCA3 test was superior to the blood PSA test in detecting prostate cancer, Ho suggests that the dual marker could be used as a surveillance test after repeat negative prostate biopsies or as an adjuvant to the serum PSA test to improve prostate diagnosis.

Ho is currently continuing patient recruitment to generate a larger sample size for future testing. "If the AMACR-PCA3 screening method becomes a standard in the diagnosis of prostate cancer, it would have a profound effect on millions of men," she said.

Citation: Ouyang B, Bracken B, Burke B, Chung E, Liang J, Ho SM ( NIEHS. 2009. A duplex quantitative polymerase chain reaction assay based on quantification of alpha-methylacyl-CoA racemase transcripts and prostate cancer antigen 3 in urine sediments improved diagnostic accuracy for prostate cancer. J Urol 181(6):2508-2513.

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