Aggressive PCa - Genetic Risk Factors

First Gene Marker Found for Aggressive Prostate Cancer


A genetic variant associated with aggressive prostate cancer has been discovered by researchers at Wake Forest University Baptist Medical Center. Claiming their discovery as a "first," the  scientists say  that one day genetic information may be used in combination with other factors to guide treatment decisions.

“This finding addresses one of the most important clinical questions of prostate cancer – the ability at an early stage to distinguish between aggressive and slow-growing disease,” said Jianfeng Xu, M.D., Dr. P.H., professor of epidemiology and cancer biology.

“Although the genetic marker currently has limited clinical utility, we believe it has the potential to one day be used in combination with other clinical variables and genetic markers to predict which men have aggressive prostate cancer at a stage when the disease is still curable.”

The research will be reported online this week,  Jan. 11-15, in the Proceedings of the National Academy of Sciences. Previously, Canadian researchers in  discovered a higher risk of death from prostate cancer in patients carrying a faulty variant of the BRCA gene.

Prostate cancer accounts for one-fourth of all cancer diagnoses in the United States. Autopsy studies suggest that most aging men will develop prostate lesions that, if detected clinically, would be diagnosed as cancer.

Although most men have a slow-growing form of the disease, aggressive prostate cancers are currently the second-leading cause of cancer death in the U.S., accounting for 27,000 deaths annually.

“The current inability to accurately distinguish risk for life-threatening, aggressive prostate cancer from the overwhelming majority of slow-growing cases creates a treatment dilemma,” said Xu.

While researchers, including Xu’s team, have identified multiple genetic variants associated with the risk of developing prostate cancer in the first place, until now there have been no genetic factors associated with disease aggressiveness.

Based on existing evidence that some men are genetically predisposed to developing aggressive prostate cancer, the researchers hypothesized that inherited genetic variants exist that could be used as markers to identify these men at an early, curable stage of disease.

“Identifying factors that are associated with a risk of having or developing aggressive disease is urgently needed to reduce over-diagnosis and over-treatment of this common cancer,” said Karim Kader, M.D., Ph.D., a Wake Forest Baptist urologist specializing in prostate cancer and a co-author on the paper.

The study involved the analysis of genetic information from 4,849 men with aggressive disease and 12,205 with slow-growing disease to determine if the men with aggressive disease had genetic variants in common. The analysis included participants in the Genetic Markers of Susceptibility study performed by the National Cancer Institute (NCI) as well as additional study populations in the U.S. and Sweden.

The researchers identified a genetic variant (rs4054823) that was associated with a 25 percent higher risk of developing aggressive disease.

“A single variant with a moderate effect such as this is unlikely to be sufficient on its own at predicting risk,” said Xu. “But its identification is significant because it indicates that variants predisposing men to aggressive disease exist in the genome.”

He said that as more variants associated with aggressive disease are identified, it is possible that doctors could test men to determine their risk of aggressive disease not only at the time of diagnosis, but early enough in their lives to target them for increased screening.

“We speculate that a panel of variants could be an important part of developing a screening strategy that could reduce the number of men requiring screening, thereby reducing over-diagnosis, while also identifying men at risk for developing aggressive disease at a stage when the disease is potentially curable.”

Edited by J. Strax

The research was primarily funded by NCI.
Co-researchers were: S. Lilly Zheng, M.D., Jielin Sun, Ph.D., Ge Li, M.D., Lina D. Purcell, B.S., Seong-Tae Kim, Ph.D., and Fang-Chi Hsu, Ph.D., all with Wake Forest University School of Medicine; Sarah D. Isaacs, M.S., Kathleen E. Wiley, M.S., Patrick C. Walsh, M.D. and William B. Isaacs, Ph.D., all from Johns Hopkins Medical Institutions; Fredrik Wiklund, Ph.D., Jan Adolfsson, M.D., Ph.D., and Henrik Grönberg, M.D., Ph.D. all from the Karolinska Institutet in Stockholm, Sweden; Pär Stattin, M.D., Ph.D. from Umeå University Hospital in Umeå, Sweden; Jeffrey M. Trent, Ph.D., David Duggan, Ph.D., and John Carpten, Ph.D., from Translational Genomics Research Institute in Phoenix, Ariz.; and Jonas Hugosson, M.D., from Sahlgrenska University Hospital, Goteborg, Sweden.

Wake Forest University Baptist Medical Center ( is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children’s Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university’s School of Medicine and Piedmont Triad Research Park. The system comprises 1,056 acute care and rehabilitation beds and has been ranked as one of “America’s Best Hospitals” by U.S. News & World Report since 1993. Wake Forest Baptist also holds the Gold Seal of Approval™ from the Joint Commission, the nation’s esteemed standards-setting and accrediting body for health care quality. Wake Forest Baptist is ranked 32nd in the nation by America’s Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.


Aggressive PCa - Genetic Risk Factors