The Continuing Search for Risk Markers

This article is based upon a study* supported in part by the URF and presented at a recent American Urological Association meeting.

PSA is the long-standing and accepted method for early detection of prostate cancer and for recommendation of biopsies; yet, it is not perfect.

Other biomarkers are needed which can distinguish the type of prostate cancer – indolent or aggressive disease.

Dr. Catalona and his research collaborators, supported in substantial part by donations to the Urological Research Foundation, continue to focus their studies on the genetics of prostate cancer.

Allele: one of the altered forms of any segment of a chromosome.

Researchers look at specific DNA codes of known genes and at variations within these genes called alleles.

Most people have seen the very long and involved list of alphabet letters that represent a genetic code. In one area, a part of a code might be CCATT but in a substantial number of men with prostate cancer, that code is CAATT.

The place where the changed code is spotted (in this example, it is the second letter; C to A) is called an allelic or allele variation.

Effect Is Cumulative

Within the past several years, genome studies have identified about 35 independent prostate cancer risk alleles which increase a man’s odds of developing the disease.

While each of these risk alleles is only modestly associated with prostate cancer risk, together and along with family history, they work in concert to greatly increase disease susceptibility.

Each one of the 35 risk alleles only modestly increases the risk of prostate cancer; however cumulatively, these variants act together with family history to increase the risk of CaP by 9-20 times.

While the association between the risk allele and disease susceptibility is now widely accepted, it is currently unknown whether the risk alleles can provide information regarding disease susceptibility in a population of men with seemingly nonthreatening disease defined by a “normal” PSA (less than 4.0) and a non-suspicious digital rectal exam.

In addition, it is unknown whether any of these risk alleles can provide information regarding adverse pathology features in this same group of men.

Providing Diagnostic Information

To answer these two concerns, this study identified 203 **Caucasian patients (Catalona) who underwent a prostatectomy for clinical stage T1 disease, had a “normal” PSA defined as less than 4.0, and a non-suspicious digital exam. Thus, these patients had no obvious features that were concerning for prostate cancer.

The comparison group was 611 Caucasian men who had a PSA less than 4, a non-suspicious digital exam and no present diagnosis of CaP.

All the participants were genotyped for 17 independent risk alleles. The study determined the cumulative risk associated with these alleles and/or the presence of a positive family history.

Finally, the study determined the frequency of adverse pathology features among carriers of the risk alleles.

In men who have a normal PSA and a normal exam, and no other identifying features, an increased risk is present for CaP associated with carrying an increasing number of risk factors.

For example, if an individual had more than 10 risk alleles, as was the case for 20% of cases and 3% of controls, there was over an 11 fold increased risk of having prostate cancer.

The importance of this finding is that men who had more than 10 risk alleles, but no other identifying features for prostate cancer, had an 11-fold risk of cancer.

The study compared the frequency of adverse pathology features in men who were carriers and non-carriers. Three of the risk alleles were over-represented in men with adverse pathology; however, a trend among men who were carriers of one of the risk alleles along chromosome 8 (8q24) is to have worse pathological features compared to noncarriers including: higher Gleason scores, and a greater chance for positive surgical margins, seminal vesicle invasion, and lymph node involvement.

With the support of the URF, deCODE genetics, Inc, and the AUA, Brian Helfand, MD, the lead author of this study continues to study 8q24 susceptibility alleles.

Summary

Risk alleles that are over-represented in men with prostate cancer act in a cumulative manner.

Specifically, white men with more than 10 risk alleles have over an 11-fold increased risk of having prostate cancer, even with a PSA value of less than 4.

Some of the risk alleles were significantly over-represented in patients and may be associated with adverse pathology features.

Future incorporation of these risk alleles into prostate cancer screening programs should be considered.

In addition, given their potential association with adverse pathology, some of the risk alleles may eventually be used to help identify the appropriate patients for active surveillance and/or chemoprevention.