BioWorld International Correspondent

LONDON - DeCode Genetics Inc. anticipates having a DNA test available within two years that will identify men who carry a genetic variant that puts them at higher risk of developing prostate cancer.

The discovery of the variant, which lies on chromosome 8, also will help scientists studying the causes of prostate cancer. Although no one knows the function of the gene that is affected, initial studies already have shown that it is expressed in the testis.

Kari Stefansson, CEO and founder of DeCode, of Reykjavik, Iceland, told BioWorld International, "The variant provides a spectacular genetic marker for the development of DNA-based predictive tests." Until now, he said, the only firmly established risk factors for prostate cancer have been age, family history and ethnicity.

"This discovery sheds considerable light on a man's risk of developing prostate cancer, and on the ethnic differences in this risk," Stefansson added. "A test will not tell a man if he will or will not get prostate cancer, but it will tell him if he has inherited a disposition to the disease, and he can alter his attitude to screening and follow-up accordingly. As this variant also appears to be associated with the development of more aggressive prostate tumors, a diagnostic test for the variant may enable doctors to make more informed decisions as to how closely they should monitor those who are at high risk, and how aggressively they should treat the disease once it presents."

The variant was first identified in an Icelandic population and then confirmed in several American and Swedish cohorts. Men who carry the variant have a 60 percent increased risk of developing prostate cancer. Furthermore, among men who have prostate cancer, those with more malignant grades of the cancer are more likely to have the variant than those with more benign forms.

Among European American men with prostate cancer, the variant accounts for about 8 percent of cases, whereas, among African-American men, it accounts for about 16 percent of cases.

The difference in prevalence of the variant in African-Americans could account in part for the observation that African-American men are 1.6 times more likely to develop prostate cancer than European American men, and 2.4 times more likely to die from it if they do develop it.

Stefansson and his collaborators reported their study in the May 7, 2006, issue of Nature Genetics in a paper titled "A common variant associated with prostate cancer in European and African populations."

The team analyzed DNA from 3,430 men with prostate cancer and 2,675 controls. They identified two alleles on chromosome 8, called rs1447295 A and DG8S737-8. Neither, on its own, can fully explain the higher risk observed among those men who carried them. Although the authors postulated that the -8 allele is the causative allele, men whose chromosomes had both alleles had the highest risk of prostate cancer.

The authors recommended that replication studies should investigate both markers in populations of European ancestry. In African-Americans, however, the researchers suggested that the -8 allele alone could produce more than a 10 percent greater incidence of prostate cancer than in European Americans.

Biologically, the finding fits with what is known of the causes and influences of prostate cancer. Studies have shown that the chromosomal region 8q24, where the variant is found, is commonly duplicated in prostate tumors. That phenomenon tends to be associated with aggressive tumors and poor prognosis.

In the characterization of prostate cancer, a high Gleason score (7 to 10) indicates that the disease is more aggressive. The study found that the frequency of the -8 allele was significantly greater in men with prostate cancer and a Gleason score of 7 or greater, than in controls. The frequency of that allele also was greater in those with prostate cancer and Gleason scores of 7 or more than in those with low Gleason scores (2 to 6), although that difference was more modest.

In 510 Icelandic men diagnosed with benign prostatic hyperplasia, but not prostate cancer, there was no statistically significant excess of either allele -8 or rs1447295 A.

The -8 allele is situated close to the well-known oncogene c-MYC. There were, however, no significant correlations between single nucleotide polymorphisms located in the c-MYC gene and the risk of prostate cancer.

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