Researchers may have found a way to refine prostate cancer screening and diagnosis by helping doctors interpret the meaning of a man's PSA reading.

PSA, or prostate-specific antigen, is a protein produced by the prostate gland. Levels of PSA in the blood are elevated in men with prostate cancer, but there is uncertainty about just how much is too much. Many doctors use 4 nanograms per milliliter of blood as a cut off point to determine which men need a prostate biopsy to search for cancer.

But doctors have always wondered why some men have high blood levels of PSA, yet do not actually have prostate cancer when a biopsy is performed.

Now, in a paper published in the Journal of the National Cancer Institute (Vol. 95, No. 14: 1044-1053), researchers from Wake Forest University Medical School show that a small chemical change in the genes responsible for PSA production can affect its blood levels.

According to lead researcher Scott Cramer, PhD, knowing a man's genetic makeup may help him avoid a needless biopsy to look for prostate cancer. High PSA levels may be normal for men with the unusual genes -- not a sign of cancer.

Two genes control PSA production by the prostate gland. One gene makes the protein itself. The second gene, which was the focus of Cramer’s study, controls how much PSA is made. This is called the promoter gene.

Cramer and his colleagues studied the PSA promoter gene in 409 healthy white men who were checked for prostate cancer after on-the-job exposure to asbestos. They looked at the chemical makeup of the gene in each man and compared it to his blood PSA level. Because a person's genes are all the same no matter which part of the body they come from, the researchers were able to analyze circulating white blood cells, and no prostate biopsy was needed.

Researchers found that the men's genes differed because of simple changes called single nucleotide polymorphisms, or SNPs. They discovered eight important SNPs. Men with some of these SNPs had higher PSA levels, while men with the others had lower levels. None of the men had prostate cancer.

Although each SNP alone could affect the PSA level, they were more potent in certain combinations. One particular combination produced PSA levels 50% greater than another combination, for instance.

In the future, the researchers said, genetic testing could identify each man's personal "normal" PSA level. That could help doctors determine when a man's PSA really is too high, and when he might need a prostate biopsy to look for cancer.

Yet even with this discovery, many questions about early detection of prostate cancer remain.

Writing in an editorial accompanying the study, University of Texas urologist Ian Thompson, MD, and his colleagues agree that polymorphisms should be used to determine a person's "normal" PSA level.

But they raise a chicken and egg question, too. Do the polymorphisms simply cause PSA levels to rise, or are PSA levels higher in response to other ways these genes act -- ways that may increase a man's risk of prostate cancer. The editorial writers feel that this needs further exploration.

And the researchers themselves acknowledge that more study is needed to determine whether these gene changes have the same effect in men of different races, whose prostate cancer risk may be different. (African-American men, for instance, have a greater risk for prostate cancer than white men.)

Whatever the answer, the editorialists and researchers agree that better techniques are needed for accurately diagnosing prostate cancer.