More Evidence Ties Chromosome Region to Prostate Cancer
Five new studies are reporting that a region of chromosome 8 contains genetic variations that may increase a man's risk of developing prostate cancer.
The specific variants responsible for the risk have not yet been found, and the biological mechanism underlying the effect is not yet known. But researchers have identified genetic markers that are strongly associated with the disease, and they have a flood of data demonstrating the association in different populations.
"This region has a lot of variation that differs within and among men of different ethnic backgrounds, and these changes may have important effects on prostate cancer risk," says Dr. Stephen Chanock, director of the NCI Core Genotyping Facility and co-leader of an NCI study.
"With so many new studies, we can clearly see that this region may be an opportunity to learn which variations are important to different groups," Dr. Chanock adds.
His team scanned the genomes of more than 1,100 individuals with prostate cancer and 1,100 matched controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study. In the region, the researchers identified a risk variant first reported last year and a second variant nearby that acts as an independent risk factor in men of European descent.
The new variant (called rs6983267) may account for 20 percent of prostate cancers among white men in the United States, the researchers estimate. Their study was one of three published together online in Nature Genetics on April 1.
Dr. Kari Stefansson of deCODE Genetics in Iceland, whose team discovered the first variant (rs1447295) in the region last year, led the second study. They have now identified a second variant that contributes significantly to the risk of prostate cancer in four populations of men of European descent.
The third study, funded in part by NCI and led by Drs. David Reich of the Broad Institute at Harvard and MIT and Christopher Haiman of the University of Southern California (USC), identifies seven genetic variants associated with prostate cancer risk in three distinct parts of the region, called 8q24.
Nearly all of the variants were most commonly found in African Americans and may contribute to the higher rate of prostate cancer among this group compared with other U.S. populations. Certain combinations of the variants were associated with a fivefold increase in risk for African Americans.
Age, ethnicity, and family history are known to play a role in prostate cancer. But for more than a decade, efforts to find susceptibility genes have largely been unsuccessful.
"These are really the first bona fide genetic risk factors for prostate cancer," says Dr. Haiman, the lead author of the USC-Broad Institute report. "There is now an overwhelming amount of support for genetic variation in the region contributing to this disease."
The April 1 issue of Cancer Research has two additional reports on 8q24. One study estimates that white men who carry two copies of the rs1447295 variant have a 90-percent increased risk of prostate cancer compared to men without the variant. The study included 6,600 cases of prostate cancer and 7,300 controls from the NCI Breast & Prostate Cancer Cohort Consortium.
"We have never observed such consistency for prostate cancer genetics, not among linkage studies, not among association studies, and certainly not when combining all these approaches together," writes Dr. Elizabeth Platz of the Johns Hopkins Bloomberg School of Public Health in an accompanying commentary.
Quite unexpectedly, the research community has found multiple regions in the same part of the chromosome that influence prostate cancer, notes Dr. Gilles Thomas, senior author of the NCI study and co-leader of CGEMS. "And what is striking is that we don't have any good candidate genes there."
The region contains very few genes. The variants, which are single nucleotide polymorphisms (SNPs) - places in the genome where a single unit of DNA may vary from one person to the next - do not fall within or near genes, so the mechanism responsible for the risk remains a puzzle.
"We suspect that the region may contain genetic elements such as microRNAs, which can regulate the activity of key genes," says Dr. Chanock.
"It's an exciting time," adds Dr. Brian Henderson, dean of the school of medicine at USC. "We need our basic science colleagues to help us understand what this signal is all about."
Whatever the answer turns out to be, he says, it will be brand new information that could revolutionize the treatment and prevention of prostate cancer and have implications beyond this disease.
"The answer will probably be a surprise, and that's why it will be so fascinating and important - because we didn't expect it," says Dr. Henderson, a senior author of the USC-Broad Institute study.
By Edward R. Winstead