Discovery enabled by collaborative effort of scientists at more than a dozen institutes in U.S. and Sweden

In treating prostate cancer patients, clinicians agree: no one size of treatment fits all. With more than 25 genetic subtypes of this cancer already identified by PCF-associated researchers at the University of Michigan, we not only know that there are indeed varieties that a man might die with and not of while, while other varieties require immediate aggressive treatment, but we are zeroing on which genotypes require aggressive treatment. For decades, our inability to differentiate definitively between the two groups, as well as those in between, has resulted is an estimated $2 billion in overtreatment each year. Not only is this an unnecessary burden on the U.S. healthcare system, such overtreatment can needlessly subject many men to the numerous life-changing side effects that treating this disease can impart.

We may now be steps closer to alleviating this problem and improving treatment for the more than 240,000 men in the U.S. alone who will be diagnosed with prostate cancer this year.  

Janet L. Stanford, Ph.D. at the Fred Hutchinson Cancer Research Center is a PCF-funded investigator. She and a team of scientists from Seattle to Sweden have identified a 5-gene signature for lethal prostate cancer. The findings, published online ahead of the September issue of Cancer Epidemiology, Biomarkers and Prevention, might serve as the basis for a new blood test that could be given on initial diagnosis in order to determine which patients need aggressive treatment versus watchful waiting.

“Being able to accurately stratify a patient’s disease, predict outcome and direct them to the appropriate treatment would empower us to cure more and overtreat less,” explains Jonathan W. Simons, MD, president and CEO of the Prostate Cancer Foundation. “What’s more, bringing more assurance to the diagnostic, staging and treatment process may also bring more confidence and clarity to patients and their families as they are force to navigate through a very difficult time.        

To discover the five “disease genes” implicated in lethal prostate cancers, Dr. Stanford and her colleagues looked for genetic variants that men with prostate cancer share in common. Called single-nucleotide polymorphisms, or SNPs (pronounced “snips”), these inherited genetic variants are certain genes in the whole prostate cancer human genome that may code—or signal—the development of fatal varieties of the disease. The five SNPs Dr. Stanford identified were linked to five genes that may affect prostate cancer progression: namely, LEPR, RNASEL, IL4, CRY1, and ARVCF. 

Dr. Stanford explains that her team “chose to study SNPs in genes that potentially play a key role in biological pathways that may contribute to prostate cancer progression such as inflammation, steroid-hormone production and metabolism, DNA repair, circadian rhythm and vitamin D activity.” With approximately 20% of all human cancers linked to chronic infections and chronic inflammation, the finding associating two of the five genes studied (IL4 and RNASEL) with prostate inflammation may play a part in better understanding whether there is an infectious agent that triggers early prostate cancer. The identification of Helicobacter pylori as an unrecognized infectious cause for stomach ulcers and stomach cancer transformed the entire direction of research around early diagnosis and prevention of gastric cancer.

To find the panel of markers associated with lethal prostate cancer, the scientists studied a population-based group of 1,309 Seattle-area prostate cancer patients who were age 35 to 74 at the time of diagnosis. They investigated 937 SNPs in 156 candidate genes. Of these, 22 SNPs  stood out as being associated with more fatal forms of prostate cancer. This result, found through analysis of DNA in blood samples, was compared to a validation study conducted in another population-based group of 2,875 prostate cancer patients in Sweden who were age 35 to 74 at diagnosis. Five of the 22 SNPs were identified in this Swedish study as being implicated in prostate cancer mortality. 

The Prostate Cancer Foundation laid the groundwork for genetic studies of this kind through its early work collecting blood from patients and families with prostate cancer for genetic studies in 1994. It provided key funding to help establish the family-based study called the Prostate Cancer Genetic Research Study--PROGRESS. Recognizing the lack of research findings on the causes of prostate cancer and the emerging evidence that a family history of the disease conveyed an increased risk, Dr. Stanford and colleagues Drs. Elaine Ostrander and Lee Hood tackled this problem by initiating the PROGRESS study. 

The problem of little research addressing the issue of the inherited causes for prostate cancer was close to home for Dr. Stanford. Family ties led her to become a prostate cancer researcher. After learning her father had been diagnosed with the disease in 1984, she questioned what variable risk factors might have caused his prostate cancer. She realized quickly that there was little research to address this issue. 

“There was very little support for prostate cancer research during the 1970’s and 80’s—few investigators were doing it,” says Dr. Stanford, co-Head of Program in Prostate Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle. “Back then the assumption was that almost 100% of men would develop prostate cancer in their lifetime, but they wouldn’t develop it until they were quite elderly and would die from some other cause.”

In 1995, PROGRESS gained considerable momentum after PCF founder and Chairman Mike Milken made a public appeal to viewers on nationally-televised Larry King Live. With a 1-800 number scrolled at the bottom of television screens during the interview, Milken urged those who had a family history of prostate cancer to call and be a part of the study.

According to Dr. Stanford, Milken’s appearance resulted in thousands of phone calls throughout the night of the broadcast. She and her staff had to forward calls to voicemail after inquiries about the study continued to pour in up until the wee hours of 2 a.m.

“The Larry King Live Show was the best recruitment tool ever,” said Dr. Stanford. “The 1-800 number made it easy for people to contact us directly, and it didn’t require them to get a physician’s referral. PCF’s funding was critical, absolutely critical for starting this research,” said Dr. Stanford. “PROGRESS would have never happened if it weren’t for that initial funding. That support went towards the first critical stages of collecting the families’ information, collecting the blood samples and getting them processed, and making the DNA available to researchers for genotyping.”

Sixteen years later, the impact of PROGRESS lives on in Dr. Stanford’s work identifying the inherited genetic variants for lethal prostate cancer. It may forever change clinical decision-making and vastly improve the quality of life for prostate cancer patients and their families.

The next step is to conduct further studies evaluating the use of the 5-gene signature in other patient populations and continuing to characterize other genetic mutations that might be useful for stratifying patients for more effective and efficient clinical decision-making.   

Moving More Biomarker Studies Forward with MOVEMBER

Extending on our commitment to global collaboration to find better diagnostic tools like the 5-gene signature, PCF is leading the U.S. team in the Movember Global Action Plan (GAP). The overall goal of the two-year GAP research program is to better predict aggressive disease and to characterize metastatic biology and treatment resistance by identifying clinical biomarkers that ultimately enhance treatment decisions. This will be achieved through analysis and correlation of patient materials (tissue, urine, circulating tumor cells, serum and exosomes).  We hope to accelerate progress and  the use of potentially novel biomarkers of early detection.

Movember will create a Wiki-type global docking page for all biomarker discovery scientists where the standard operating procedure is to verify published papers, bio-repository inventories are transparent for collaboration, and postdoctoral students can communicate with one another. Creating an on-line "knowledge exchange" between laboratories around biomarker discovery and validation will foster additional collaboration and accelerate more discovery in genetic biomarkers.

The Global Team: Collaborators on the study included researchers from the Karolinska Institutet in Stockholm; Umea University in Umea, Sweden; the National Human Genome Research Institute of the National Institutes of Health in Bethesda, Md.; Wake Forest University School of Medicine in Winston-Salem, N.C.; and Johns Hopkins University in Baltimore.

The research was conducted via the National Cancer Institute-funded Pacific Northwest Prostate Cancer Specialized Program in Research Excellence, which is co-led by Stanford and based at the Hutchinson Center. Additional support was provided by the Hutchinson Center, the National Human Genome Research Institute, the Cancer Risk Prediction Center, the Swedish Research Council, the Swedish Cancer Foundation, the Hedlund Foundation, the Soderberg Foundation, the Enqvist Foundation and the Stockholm City Council.