Mixing genetic profiling with PSA data to project prostate cancer risk


There was a report on the AP news service yesterday which suggested that, “Scientists have taken a first step toward improving those problematic PSA tests for prostate cancer, by mixing in some genetic information that might help tell which men really need a biopsy.”

The AP report was based on an article by Gudmundsson et al. in the new journal Science Translational Medicine and on a media release from deCode Genetics. It appears there were multiple reasons for giving publicity to the findings reported in this article.

The paper by Gudmundsson et al. announces the discovery that a set of “single-letter variations” in human DNA can affect individual baseline levels of PSA, In other words, just for example, the substitution of an adenosine nucleotide (A) for a thymidine nucleotide (T) at a specific point in human DNA may significantly affect whether a man’s baseline PSA is “normally” 0.7 ng/ml at age 40 or still “normal” but much higher.

Clearly this is interesting. If we can demonstrate that men with a specific genetic makeup consistently have a “normal” PSA level of (say) 3.5 to 4.0 ng/ml as opposed to < 1 ng/ml, then we do not need to biopsy these men under normal circumstances to assess their risk for prostate cancer — because their PSA level is not indicating a risk. However, the Devil will very clearly be in the details.

How specific (accurate) is this genetic profiling … 70 percent accurate? 80 percent accurate? 99 percent accurate? If it is not extremely accurate, then a specific man’s elevated PSA may still be associated with significant risk for prostate cancer — despite the genetic profile.

According to the CEO of deCode Genetics, the company “plans to develop a test for those genetic markers, perhaps later next year, in hopes that doctors could use the information to customize how they read and react to their patient’s PSA test results.” The “New” Prostate Cancer InfoLink thinks that’s a lovely idea — but we certainly wouldn’t recommend that any patient or doctor did this outside of a well-defined, prospective clinical trial. The available data is simply not sufficiently informative.

We would also point out that this test does nothing to help identify men with clinically significant as opposed to indolent forms of prostate cancer. Here we are in full agreement with Dr. Otis Brawley of the American Cancer Society, who is quoted by the AP as saying, “What we desperately need is some type of test … that tells us, ‘This is the kind of prostate cancer that kills’ versus the kind of cancer that doesn’t kill” men at the time of initial diagnosis.

The actual paper by Gudmundsson et al. discusses the initial use of PSA and genetic data from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. The authors say that they were able to demonstrate a clear association between PSA levels and single-nucleotide polymorphisms (SNPs) at six specific places on the human genome. They then showed that among 3,834 men who had had a prostate biopsy, the presence of three of the SNP alleles that associate with high PSA levels were associated with a higher probability of a negative biopsy (odds ratio,1.15 to 1.27). (We would note that an odds ratio of 1.15 to 1.27 equates to a relative increase in probability of 15 to 27 percent, which is not exactly huge.)

Finally, Gudmundsson et al. studied the association between the six SNP loci and prostate cancer risk in 5,325 prostate cancer patients and 41,417 controls from Iceland and four other countries. They were able to show that the SNPs at two of the loci were exclusively associated with PSA levels, whereas the SNPs at the other four loci were associated with PSA levels and prostate cancer risk.

The authors then “propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.” However, in an editorial comment in the same issue of Science Translational Medicine, Dr. John Witte of the University of California, San Francisco makes the rather more conservative comment that, “These findings are an important step toward incorporating genetic markers into PSA screening, with the ultimate goal of devising personalized PSA tests for use in the clinic.”

The “New” Prostate Cancer InfoLink is right there with Dr. Witte. These findings are indeed an important step toward personalized assessment of risk for prostate cancer, but that does not imply that a test based on these findings (as proposed by deCode Genetics) is ready for broad use in the clinic, by any manner of means. We believe it is critical that this type of genetic profiling be subjected to appropriate prospective clinical trials to establish the specificity of the proposed test before it is made available for broad clinical use.

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