Photo by Susie Fitzhugh
An international team of researchers led by Dr. Janet Stanford, co-director of the Hutchinson Center’s Program in Prostate Cancer Research, has identified five inherited genetic variants that are strongly associated with aggressive, lethal prostate cancer. The discovery ultimately could lead to the development of a simple blood test that could be given upon diagnosis to determine which men should receive aggressive treatment versus a more conservative "watchful waiting" approach.
The findings appeared online Aug. 16 ahead of the September issue of Cancer Epidemiology, Biomarkers and Prevention.
The burden of overtreating indolent prostate cancer
A substantial number of men with indolent tumors—which have a low probability of progressing to clinically significant prostate cancer—are overtreated and, as a result, suffer side effects such as sexual impotence and urinary incontinence. Overtreatment of indolent prostate cancer also carries a substantial economic burden, with an average of $2 billion to $3 billion spent annually in the U.S. on initial therapy alone.
"Biomarkers that could distinguish between patients with indolent versus more-aggressive tumors are urgently needed," said Stanford of the Public Health Sciences Division. "The panel of markers we’ve identified provides the first validated evidence that inherited genetic variants play a role in prostate cancer progression and mortality."
The panel of five single-nucleotide polymorphisms, or SNPs (pronounced "snips"), are single-letter variations within the four-letter DNA alphabet that serve as markers of genetic variation across the genome and may play a role in the development or progression of disease.
From Seattle to Sweden
For the study, the researchers analyzed DNA in blood samples taken from a population-based group of 1,309 Seattle-area prostate cancer patients who were age 35 to 74 at the time of diagnosis. They evaluated 937 SNPs in 156 candidate genes and, of these, 22 SNPs emerged as being significantly associated with prostate cancer-specific mortality.
A subsequent validation study of these 22 SNPs was conducted in another population-based group of 2,875 prostate cancer patients in Sweden who were age 35 to 74 at diagnosis. Upon genotyping DNA from their blood, five of the 22 SNPs emerged as being significantly associated with death from prostate cancer. A higher proportion of patients from Sweden (17.4 percent) had died of prostate cancer relative to those from Seattle (4.6 percent) during a median follow-up period of 6.5 years, which is consistent with the higher prostate cancer mortality rate in Sweden relative to the U.S.
The five SNPs were located in or tagged, one each, to five genes that may affect prostate cancer progression:
- LEPR – The strongest marker associated with prostate cancer mortality in the study was the leptin receptor gene, which helps control tissue growth, inflammation, blood-vessel development and bone density.
- RNASEL – This gene is associated with hereditary prostate cancer and is associated with apoptosis (programmed cell death), inflammation and the ability of cells to proliferate and stick to each other.
- IL4 – This Interleukin 4 gene is associated with tumor growth, blood vessel development and cancer cell migration.
- CRY1 – Cryptochrome 1 is a gene that impacts the circadian rhythm and thereby may affect androgen levels, which are known to be involved in prostate cancer progression.
- ARVCF – This gene is a member of the catenin family of proteins, which help the inside and outside of cells “talk” to each other. Increased expression of ARVCF has been shown to disrupt cell adhesion, which may facilitate cancer progression.
Patients who carried four or all five of these genetic markers had a 50 percent higher risk of dying from their prostate cancer than patients who had two or fewer. The risk of dying from prostate cancer increased with the number of SNP genetic variants a patient carried.
Improving prostate cancer treatment
"While previous studies have suggested that genetic background influences prostate cancer outcomes, this is the first study to validate genetic markers associated with lethal disease," Stanford said. The findings could lead to better care for those with aggressive, life-threatening prostate cancer and help avoid overtreatment of patients with indolent tumors.
The researchers will now evaluate the potential clinical usefulness of the panel of five SNPs in other patient populations. Stanford and colleagues will also study the genetic markers to predict adverse prostate cancer outcomes.
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. Read more about the study and collaborators in the Center’s news release.