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Researchers identify new gene changes that point to elevated prostate cancer risk

June 11, 2018

As the result of a six-year long research process, Fredrick R. Schumacher, PhD, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings, published in a research letter in Nature Genetics, contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.

The changes, known as genetic markers or SNPs ("snips"), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G), and cytosine (C). The order of these bases determines DNA's instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are three billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.

One in seven men will be diagnosed with prostate cancer during their lifetimes.

"Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions," said Schumacher. PSA is a blood test used to screen for prostate cancer. It measures the amount of prostate-specific antigen (PSA) in the blood. PSA is a protein produced by both cancerous and noncancerous tissue in the prostate.

Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.

In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn't have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.

The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. "We probably only need to know ten percent to twenty percent of these to provide relevant screening guidelines," continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at CWRU.

Currently, researchers don't know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for "watchful waiting" and monitoring.

The research lays a foundation for determining who and how often men should undergo PSA tests. "In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening," said Schumacher. "We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every 2-5 years." A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. "Someday it may be feasible to target treatments based on a patient's prostate cancer genetic risk score," said Schumacher.

In addition to the work in the new study, which as noted, targets men of European background, there are parallel efforts underway looking at genetic signals of prostate cancer in men of African American and Asian descent.
-end-
Funding for the research was provided by the US National Cancer Institute (GAME-ON study, Genetic Associations and Mechanisms in Oncology), the US Department of Defense, the European Commission's Seventh Framework Program, Cancer Research UK, the Canadian Institutes of Health, the Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.

Schumacher, F., et al. "Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci." Nature Genetics. doi:10.1038/s41588-018-0142-8

For more information about Case Western Reserve University School of Medicine, please visit case.edu/medicine.

Case Western Reserve University

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