Polymorphisms may contribute to variations in PSA levels

July 15, 2003

Polymorphisms in the promoter region of the prostate-specific antigen (PSA) gene may contribute to individual variations in PSA levels, according to a study in the July 16 issue of the Journal of the National Cancer Institute.

Use of PSA testing in prostate cancer screening has been limited by its lack of sensitivity and specificity. Men with a serum PSA level greater than 4 ng/mL are typically referred for a prostate needle biopsy. However, factors such as benign prostate disease, age, and race contribute to individual variations in PSA level, making it difficult to determine which patients should undergo further testing.

Genetic polymorphisms in the PSA gene have also been associated with serum PSA level. In a past study, researchers identified a single nucleotide polymorphism (SNP) in the PSA gene promoter that was associated with increased serum PSA levels in healthy men. However, this polymorphism was later found not to be associated with PSA level in two different groups of healthy men.

To examine additional polymorphisms in the PSA gene that may contribute to variations in PSA level, Scott D. Cramer, Ph.D., of the Wake Forest University School of Medicine in Winston-Salem, N.C., and his colleagues examined PSA genes of 409 healthy white men at risk for lung disease. They identified three specific SNPs, -4643A/G, -5412T/C, and -5429T/G, in the promoter region of the PSA gene that were associated with increases in serum PSA levels.

"The results of the current study suggest that genotyping SNPs in the far upstream region of the PSA gene may improve the sensitivity of PSA testing for prostate cancer," they write.

The authors suggest that future studies should examine whether these polymorphisms can be used to help to determine PSA cutoff values for further testing by prostate needle biopsy. The new findings suggest that the cutoff value for a man with a PSA promoter genotype associated with reduced serum PSA levels may be lower than that for a man with a genotype that is associated with elevated serum PSA levels.

"Our results suggest that the SNPs in the far upstream enhancer region of the PSA gene may be good candidates for incorporation into a genetic model for prostate cancer risk," the authors write.

In an accompanying editorial, Ian M. Thompson, M.D., of the University of Texas Health Science Center at San Antonio, and his colleagues caution that "we cannot be certain whether these polymorphisms directly affect PSA levels in men or whether they increase the risk of prostate cancer and thereby (indirectly) increase PSA levels. Clearly the role of PSA in prostate cancer detection needs further exploration."

They continue, "although PSA has had a profound effect on the identification of prostate cancer, this study demonstrates the need to constantly refine and improve this important diagnostic tool and to explore other diagnostic modalities."
Contact: Karen Richardson, Wake Forest University School of Medicine, 336-716-4453; fax: 336-716-6841, krchrdsn@wfubmc.edu

Editorial: Will Sansom, University of Texas Health Science Center, 210-567-2579, sansom@uthscsa.edu.

Cramer SD, Chang B, Rao A, Hawkins GA, Zheng SL, Wade WN, et al. Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. J Natl Cancer Inst 2003;95:1044-53.

Editorial: Thompson I, Leach RJ, Pollock BH, Naylor SL. Prostate cancer and prostate-specific antigen: The more we know, the less we understand. J Natl Cancer Inst 2003;95:1027-8.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

Journal of the National Cancer Institute

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