September 23, 2009 — New findings of multiple gene variants associated with prostate cancer susceptibility may enable risk prediction and targeted screening of high-risk individuals, according to 4 studies published online September 20 in Nature Genetics. Notable among the risk variants is a collection of loci — some reported by each of 3 independent research groups — at 8q24 on the long arm of chromosome 8.
Two international studies were led by a group of researchers in the United Kingdom. Their first genomewide association study (GWAS) identified 7 new loci associated with prostate cancer susceptibility in a 3-stage investigation, with the final stage involving 16,229 patients with prostate cancer and 14,821 control individuals. Risk loci with genomewide significance (P = 1.6 × 10−8 to 2.7 × 10−33) were found on chromosomes 2, 4, 8 (other than 8q), 11, and 22.
Several risk loci were found in or near genes such as ITGA6, which participates in cell adhesion and signaling, and NKX3.1, which codes for a protein in the HDAC1 pathway.
"This pathway is involved in chromatin modeling and is hormone driven," said lead author Rosalind A. Eeles, PhD, FRCP, FRCR, from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom, in her email to Medscape Oncology. "These inhibitors reduce cell division, which is increased in prostate cancer as a result of uncontrolled chromatin remodeling," explained Dr. Eeles.
Their second study used data from stages 1 and 2 of the previous work (5504 patients with prostate cancer, 5834 control patients) to identify prostate cancer risk loci on 8q24, the region "currently considered the most important susceptibility region for [prostate cancer], or indeed for any common cancer," the authors point out. This study found 8 independent risk variants (3 previously reported) with P values from 4.2 × 10−6 to 6.8 × 10−24.
In a genomewide association "follow-on study," scientists at deCODE genetics identified 4 additional prostate cancer risk variants, none identical to those reported above. One variant was on chromosome 3, another on chromosome 19, and 2 were in region 8q24; genomewide significance ranged from P = 6.2 × 10−15 to P = 4.7 × 10−10. This study drew on data from the Icelandic GWAS and from the replication genotyping study of the National Cancer Institute's Cancer Genetic Markers of Susceptibility project. Size of the prostate cancer and control populations differed between variants, but all exceeded 8200 and 16,900, respectively.
Region Has Important Role
"This [8q24] is a region that seems to have a very important role when it comes to controlling genetic risks for all kinds of cancers," commented senior author Kari Stefansson, MD, president and chief executive officer of deCODE genetics, Reykjavik, Iceland, in a telephone interview with Medscape Oncology. "We don't know how it does so. We don't know what fundamental biochemical perturbation is caused by variants in this region, but it is certainly one that we will be looking at." he said. "And others are working on trying to do the same."
A fourth, independent study reported the identification of a significant (P = 1.3 × 10−10) risk locus on 8q24, substantiating 1 of those identified in the paper by Eeles and colleagues, but in a larger population (10,286 patients with prostate cancer, 9135 control individuals). Interestingly, this report notes that region 8q24 contains no known protein-coding genes. "The 8q24 region is a 'gene desert,' " observed first author Meredith Yeager, PhD, from the Core Genotyping Facility, SAIC-Frederick, Inc, NCI-Frederick, Maryland, and Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, in an email to Medscape Oncology.
However, she added, "A very compelling proto-oncogene (MYC) is located downstream of this region. Already, some groups have published evidence of a functional relationship between one of the associated variants and this gene," said Dr. Yeager. "While the results are exciting, much more work is needed to explore the relationship among these variants, MYC, and other genes as well."
Medscape Oncology received comments from Charis Eng, MD, PhD, director and chair of the Cleveland Clinic Genomic Medicine Institute, and professor and vice chair of the Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio. " We have not utilized any of the prostate GWAS data for treatment because often the culprit genes are still uncertain," Dr. Eng explained in an email.
Risk Variants: Drug Targets or Screening Tools?
"Unlike other high-penetrance susceptibility genes...all these multiple GWAS-derived susceptibility genes have a very low one-to-one correlation.... When that is the case, one cannot (and should not) target drug treatment. Importantly, these are predisposition genes; ie, what kicks the disease off, but not what causes progression," added Dr. Eng. "Perhaps we should view them as helping in prevention and limiting initiation/progression and not cure."
Dr. Stefansson also feels that their 4 new risk genes are not potential targets: "I cannot say that these provide us with...targets. I think that would be a stretch to say that," he said.
The deCODE report went on to analyze all variants known to affect prostate cancer risk in Icelandic men and showed that men in the top 1.3% of the risk distribution have a 2.5-fold or greater risk compared with the population average. This represents a 30% lifetime risk of being diagnosed with the disease compared with the 12% risk of the general population of developing prostate cancer by age 75 years.
"These risk variants can identify approximately half a percent of the population of men who have over 3 times greater [risk] than the average risk in the population of prostate cancer," said Dr. Stefansson. He noted that the disease prevalence in Iceland and the United States is about 16%, which translates into a lifetime risk for prostate cancer of roughly 50% for the high-risk group.
"If you believe in the value of risk stratification, and can contain the damage from cancer, this absolutely would provide for a...test with risk stratification. You can find men who are at 50% risk of developing the disease. So that is what I see as the most important value of these discoveries," he emphasized. "Let's put it this way: If our society concludes that we should screen for prostate cancer, this is probably the best way to make that task manageable."
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We were just talking about this in my medical billing and coding school. Very interesting stuff.
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