Multiple Gene Variants Identified in Association With Prostate Cancer Risk

Roxanne Nelson

February 15, 2008

February 15, 2008 — At least 10 new genetic variations associated with an increased risk for prostate cancer have been identified, researchers report. According to 3 studies that were published online February 10 in Nature Genetics, the number of variants known to be associated with the risk for prostate cancer has doubled.

"The implications of our results are that we are markedly nearer to being able to develop a genetic profile, which will refine prostate cancer risk," said Rosaline Eeles, MA, PhD, FRCP, FRCR, lead author of 1 of the studies and head of the Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, in Surrey, United Kingdom.

"As an example, if you take all the men in our study and their risk distribution, then 10% of men with the highest-risk genetic-profile combination in the study have a 2-fold increased risk for prostate cancer," Dr. Eeles told Medscape Oncology. "We do not yet know if such profiling will detect more aggressive disease, although our study was undertaken in clinically significant disease and not in screen-detected cases, so we would expect that these genetic variants would be clinically important."

The studies were carried out by 3 separate groups of researchers working independent of each other. In the first paper, Dr. Eeles and colleagues obtained blood samples from 1854 men in the United Kingdom who had clinically detected prostate cancer and had been diagnosed at age 60 years or younger or who had a family history of the disease. Samples were also obtained from 1894 controls aged 50 years or older with a low level of prostate-specific antigen (PSA) concentration (<0.5 ng/mL).

The researchers evaluated DNA samples from the cohort for a set of 541,129 single-nucleotide polymorphisms (SNPs), which have been estimated to report on approximately 90% of the SNPs typed in HapMap — a catalog of common human genetic variants. To confirm their results, the analysis was repeated using DNA from another 3268 men with prostate cancer and 3366 controls.

They identified 7 loci that were significantly associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19, and X, and confirmed reports of common loci associated with prostate cancer at 8q24 and 17q. In addition, they observed that 3 of the newly identified loci contain the candidate susceptibility genes MSMB, LMTK2, and KLK3.

"One of the genetic variants we found is close to the start of the code of gene MSMB, which codes for a marker," said Dr. Eeles. "This needs to be assessed to see if it is superior to PSA. Another variant is within a kinase, which could be a drug target."

However, Dr. Eeles emphasized that it is still premature to consider marketing genetic tests to the public, and further research is needed before this can be undertaken.

In the second study, Stephen Chanock, MD, and colleagues identified risk loci on chromosomes 7, 10 (2 loci), and 11, and confirmed 3 previously reported loci (2 independent SNPs at 8q24 and 1 in HNF1B). They conducted an initial genome-wide scan in a nested case control study of 1172 men with prostate cancer (484 nonaggressive and 688 aggressive prostate cancer cases) and 1157 PSA-screened controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

This was followed by 4 additional independent studies, in which 26,958 SNPs were genotyped in 4020 prostate cancer cases and 4028 controls. From the combined joint analysis, the researchers identified loci on chromosomes 7, 10, and 11 that were highly significant, and 9 other loci that are suggestive of an association with prostate cancer. They also noted that loci on chromosome 10 include MSMB, which encodes a beta-microseminoprotein that is considered to be a potential prostate cancer biomarker.

"The field is shifting and evolving and we are discovering genes that we never knew existed in prostate cancer," said Dr. Chanock, who is chief of laboratory translational genomics at the National Cancer Institute, in an interview. "We are identifying processes that are novel and important in prostate cancer."

Eventually, this information might lead to improvements in diagnosis and drug therapy, he explained. "We now have the ability to look at genetic markers and put them together with clinical information. It can help determine such things as whether a specific test should be done, the prognosis for someone diagnosed with prostate cancer, or if a specific type of treatment is more effective than another."

The third trial, a genome-wide SNP-association study for prostate cancer that included 23,000 individuals, was conducted in Iceland. This was followed by a replication study with a cohort of more than 15,500 people from Europe and the United States.

"This was a follow-up to previous work," said senior author Kári Stefánsson, MD, Dr.Med, CEO and cofounder of deCODE Genetics, in Reykjavik, Iceland. "Basically, we have uncovered about 8 loci variants that contribute to risk of prostate cancer. There are more genetic components with prostate cancer than most other cancers."

Dr. Stefánsson and colleagues identified rs5945572 on Xp11.22 and rs721048 on 2p15, which are 2 new variants that are associated with prostrate cancer. They observed that the 2p15 variant showed a significantly stronger association with the more aggressive form of the disease.

Dr. Stefánsson also pointed out that deCODE Genetics has already released a reference laboratory test for common single-letter variants that the company has associated with an increased risk for prostate cancer. The deCODE PrCa is able to detect 6 of the previously discovered SNPs that have been confirmed in many populations, as well as the 2 newly identified SNPs on chromosomes X and 2.

Nat Genet. Published February 10, 2008. Abstract (Eeles), Abstract (Chanock), Abstract (Stefansson).


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