Prostate Cancer Risk Boosted by Gene Variations Plus Family History

By Michael Smith
BALTIMORE, Jan. 16 -- The risk of prostate cancer increases dramatically in the face of five common genetic variations as well as a family history, researchers here said. Compared with men who have none of the risk factors, those with five or six are nearly 10 times more likely to develop prostate cancer, according to William Isaacs, Ph.D., of Johns Hopkins and colleagues at Wake Forest and the Karolinska Institute.The five genetic markers plus family history account for about 46% of the population-attributable risk of prostate cancer, the researchers reported online in the New England Journal of Medicine.Previous genetic variations linked to prostate cancer were associated with independent risk increases of about 10% to 40%, Dr. Isaacs said, but these markers increase risk in a cumulative fashion.

"The more of these risk factors you inherit, the higher the risk goes," he said. In this analysis, a family history of prostate cancer -- known to increase the risk of disease by a factor as high as 2.5 -- was "as important as the other risk factors," Dr. Isaacs said.
The finding builds on genome-wide association scans that revealed that five genetic regions -- three on chromosome eight and two on chromosome 17 -- were linked to an increased risk of prostate cancer.
In a case-control study in Sweden, involving 2,893 men with prostate cancer and 1,781 healthy volunteers, the researchers looked at 16 single nucleotide polymorphisms (SNPs) in the five regions that were associated with increased risk.
Analysis showed that, while each region was independent, the SNPs within a region tended to be inherited together. So the researchers chose for further study one SNP -- the one most highly associated with the disease -- within each region.
Compared with men who had none of the five genetic markers, those who carried one or more had a significant increase in the likelihood of prostate cancer, with the P-value for the trend equal to 6.75x10−27, Dr. Isaacs and colleagues found.
When family history was added, the P-value for the trend was even stronger, at 4.78x10−28.
For instance, Dr. Isaacs and colleagues reported, men who had five or more of the six risk factors -- compared with men who had none -- had an odds ratio for cancer of 9.46, with a 95% confidence interval from 3.62 to 24.72, which was significant at P=1.29x10−8.
The researchers cautioned that the six risk factors don't tell the whole story of prostate cancer, because 5% of men with the disease in the study had none of them (compared with 10.1% of the healthy volunteers).
Dr. Isaacs said it's technically relatively easy to turn the finding into a genetic test for prostate cancer risk, once the results are validated in other populations.
But he added it will be harder to decide how to use such a test, because the five genetic risk factors appear to give no information about such clinically important details as the aggressiveness of the disease, the Gleason score, the presence or absence of family history, the serum PSA level at diagnosis, or the age at diagnosis.
He said more research will be needed to see if, for example, there are genetic factors that differ between men with aggressive disease and those with indolent cancers.
The study is "further evidence that prostate cancer has complex and multifactorial origins," commented Edward Gelmann, M.D., of Columbia University in an accompanying editorial.
Like Dr. Isaacs, he cautioned that the study is only a first step, calling for prospective studies -- possibly using stored samples from some of the large prostate cancer trials of recent years -- to pin down the "true risk of prostate cancer that is incurred by this genotype combination."
He noted that among men without a family history of prostate cancer, inheriting four or five of the genetic risk factors increases the risk of disease by a factor of about 4.5.
That combination was seen in 5.4% of cases in the study, but also in 2.2% of the healthy volunteers -- implying that a test based on the genetic markers would "falsely assign more than 2% of men to a high-risk population," he said.
The study was supported by the National Cancer Institute, the Department of Defense, the Swedish Cancer Society, the Swedish Academy of Sciences, an endowment from William T. Gerrard, Mario A. Duhon, and John and Jennifer Chalsty, and the Prostate Cancer Foundation. A patent application has been filed by the Wake Forest University School of Medicine, Johns Hopkins University School of Medicine, and Dr. Henrik Grönberg at Karolinska Institutet, Stockholm, for the technology and results described in this study.
Additional source: New England Journal of MedicineSource reference: Zheng SL, et al "Cumulative association of five genetic variants with prostate cancer" N Engl J Med 2008; DOI: 10.1056/NEJMoa075819. Additional source: New England Journal of MedicineSource reference: Gelmann E, "Complexities of prostate-cancer risk" N Engl J Med 2008; DOI: 10.1056/NEJMe0708703.