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adapted for QUEST readers by Cecilia Lacks, PhD


Brian Helfand; MD, PhD presenting at the recent American Urological Association meeting.

Brian Helfand; MD, PhD presenting at the recent American Urological Association meeting.

At present, while PSA is the best diagnostic tool for early diagnosis of prostate cancer, it is not perfect for cancer detection.

Benign conditions also can cause an increase in PSA levels. In addition, higher PSA levels can cause recommendations for unnecessary biopsies while lower PSA levels can cause biopsies that are necessary to be delayed, thus compromising early cancer detection.

More Accurate Interpretations

Personalized PSA testing using genetic information can make the PSA interpretations more accurate and appropriate diagnostic recommendations more reliable.

Personalized genetic testing is now technically possible but it is often not covered by insurance and is limited because it is available in few laboratories, and few physicians are knowledgeable about how to interpret the results in clinical practice.

These conditions could change quickly with studies that show both life-saving and financial savings in treatment options.

It turns out that genetic factors affect whether men are high or low PSA producers, just as genetic factors determine if a man is short or tall.

A collaboration between Dr. Catalona’s research group with deCODE Genetics and other international research groups identified 4 SNPs associated with increased or decreased PSA levels.

These SNPs that produce high or low PSA are different from the ones that put men at risk for prostate cancer. That discovery is a recent one. Now, genetic studies of healthy men can identify the SNPs that produce high or low PSA, as opposed to SNPs that predispose men to risk for prostate cancer or for the most aggressive forms of the disease.

Recommending Biopsies Or Not

This information could assist in recommending biopsies or not.

Using the information from the collaboration, this study asked the questions:

If a man had genetically high PSA taken from the 4 “PSA SNPs,” could there be a way to correct or mathematically lower the PSA to reflect that it is actually below the threshold for recommending biopsy?

On the other hand, if a man had genetically low PSA, could there be a way to correct or mathematically raise the PSA to reflect that it is actually above the threshold for recommending biopsy?

If this genetic information could allow for adjustments in PSA testing, then recommendations for biopsy would change from present practices to more accurate ones.

A Genetic Readjustment

The method for adjusting PSA results gets complicated.

Each of the 4 PSA SNPs is represented on a chromosome in one of two different forms called “alleles.” Therefore, since there are 4 different PSA SNPs, each person has 8 PSA alleles.

For example, an individual could carry either a “P” (big P) or a “p” (small p) for each PSA SNP. There are four PSA SNP’s (1,2, 3, and 4).

For example, an individual could carry either a “P” (big P) or a “p” (small p) for each PSA SNP. There are four PSA SNP’s (1,2, 3, and 4).

A man who had 1pp, 2pp, 3pp, and 4pp would be at the lowest.

There could be multiple combinations: PP, pp, Pp, pP.

The average person has 4 large P's on the four alleles. Each of the four SNP’s has two alleles.

It is possible to make a statistical adjustment relative to the median number of the type P PSA-SNPs carried by men in the general population.

Depending upon what the genetic test shows regarding how many of these SNPs are present, that information reduces or increases the PSA to an adjusted PSA by a reduced or increased percentage.

What occurs is a genetic correction of PSA.

That genetic correction could show that a biopsy is most likely not needed even though the initial PSA reading indicated otherwise.

The opposite could also happen. The genetic correction could show that a biopsy is most likely needed even though the initial PSA reading indicated otherwise.

Changing the Numbers

This study and ones from deCODE Genetics, Inc. are showing that approximately 18-22% of PSA levels that ordinarily would be cause for recommending biopsy would be lowered to below the threshold for biopsy if personalized genetic findings were considered.

Presently, one million prostate biopsies are performed in the US annually. 180,000 to 220,000 of them might not be recommended if genetically-corrected PSA levels were used.

Incorporating these genetic corrections into clinical practice would improve the performance abilities of PSA and provide more rational personalized biopsy cut-offs.

Conclusion:

Genetic Correction for PSA-SNPs may:

  1. decrease “unnecessary biopsies” in genetically high PSA producers;
  2. increase “necessary biopsies” in genetically low PSA producers; and
  3. provide a relative reduction in total biopsies performed by 15-20%

*from AUA presentation: Personalized PSA Testing Using Genetic Variants Can Possibly Decrease the Number of Prostate Biopsies: Brian T. Helfand, MD, PhD; Stacy Loeb,MD; Matthias D. Hofer, MD, PhD; Dae Y. Kim, MD, PhD; Qiaoyan Hu, Phillip R. Cooper; Barry B. McGuire, MD; William J. Catalona, MD

Despite the recent final recommendation of the USPSTF, the URF among other organizations disputes the recommendations. See additional articles this issue of QUEST

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