Scientists at the University of California - San Francisco and Kaiser Permanente Northern California compared 7,783 men with prostate cancer to 38,595 men without the disease.
The study analysed genetic samples and health records from more than 100,000 volunteers, making it one of the largest research projects in the US to examine the genetic, health and environmental factors that influence common diseases such as prostate cancer.
The researchers modelled prostate cancer risk using 105 specific bits of DNA that commonly vary among individuals and that they confirmed are associated with prostate cancer risk.
"We developed a risk model that may have clinical value," said John Witte, a UCSF professor of epidemiology and biostatistics and of urology.
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"We also showed that there remain substantial undiscovered genetic risk factors for prostate cancer," Witte said.
Men ranked in the highest percentiles for risk in the study have a prostate cancer risk comparable to the breast cancer risk among women who carry a mutation in one of the so-called breast cancer genes, BRCA1 or BRCA2, Witte said.
The researchers also identified two new risk factors that previous studies had missed, each of which is associated with a nearly 20 per cent increase in prostate cancer risk.
One of the newly discovered risk factors - identified by the addition of just one DNA base pair at a specific location on chromosome 6 - is found in about 30 per cent of the population, yet had never been detected in previous studies of tens of thousands of men, Witte said.
The study was published in the journal Cancer Discovery.