Researchers from Sweden and the US have found that men who have five hereditary gene markers and a family history of the disease have more than nine times the risk of developing prostate cancer than men who do not.

The study is published in the January 16th online edition of the New England Journal of Medicine (NEJM) and is the work of researchers at Johns Hopkins Brady Urological Institute in Baltimore, Maryland, Wake Forest University School of Medicine in Winston-Salem, North Carolina, and the Karolinska Institute in Sweden.

The researchers, who studied data from more than 4,000 Swedish men, said the genetic markers are common and linked to nearly half of the prostate cancer cases in the study.

Their next step will be to sample an American population of men to see if these same genetic markers have such an effect outside of Sweden.

The researchers pointed out that the markers do not indicate how aggressive a cancer might be and are linked only to incidence.

Speaking about using the results for cancer screening, co-author Dr William B. Isaacs, of Johns Hopkins Brady Urological Institute, said:

“This information is not yet available as a genetic test for risk of prostate cancer, but efforts are under way to rapidly develop one.”

“While these findings need to be validated and refined, it’s a step in the right direction to revealing the genetic-based reasons for this cancer that we have been looking for over the past 15 years,” he added.

Isaacs is also William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology at the Brady Urological Institute and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

He and his co-researchers used blood samples from 2,893 men with prostate cancer and 1,781 men without the disease. They did this to get hold of white blood cells because they contain DNA that has been unaltered since birth, unlike tumour cells whose DNA is unlikely to be the same as it was at birth.

They already knew from previous research that certain single-nucleotide polymorphisms (SNPs) in five chromosomal regions (three at 8q24 and one each at 17q12 and 17q24.3) are linked with prostate cancer, but for this research they wanted to test the cumulative effect of these genetic variants.

Single-nucleotide polymorphisms (SNPs, pronounced “snips”) are small genetic changes in strips of single base nucleotides in DNA (individual building blocks called As, Ts, Gs, or Cs), that vary among individuals. For instance a SNP arranged as AAGCCTA in one person might be arranged as AAGCTTA in another.

The researchers found 16 SNPs in the five chromosomal regions were more common in men with prostate cancer than men without. Their findings confirmed previous research that had also identified these SNPs.

They then chose the most significant SNP from each of the 5 regions, confirmed that each SNP remained significant after adjusting for other SNPs and family history, and examined the cumulative effect of the SNPs on prostate cancer risk.

The results showed that:

  • Together the 5 SNPs and family history were estimated to account for 46 per cent of the prostate cancer cases in the cohort.
  • The 5 SNPs plus family history had a cumulative association with prostate cancer.
  • The more SNPs a man carried, the higher the risk that he would have prostate cancer.
  • Men with 4 or 5 of the SNPs were nearly 4.5 times more likely to have prostate cancer.
  • Counting family history as a sixth factor, men who had five or more factors (eg 4 SNPs and family history) had an even higher risk. They were over 9 times more likely to have prostate cancer, compared with those with no risk factors.
  • The cumulative effect of the SNP and family history factors was independent of serum levels of prostate-specific antigen at diagnosis (how advanced or aggressive the cancer was).

The study concluded that:

“SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer.”

Isaacs explained that their study:

“Strongly suggests that because of the combination of polymorphisms we inherit, one man may be more on the path to developing prostate cancer than another.”

And when you factor in a family history of prostate cancer, the risk effectively doubles.

It is important to note that this study did not establish a cause between the SNPs and prostate cancer. As the researchers themselves pointed out, the presence of the SNPs could be a precursor or marker linked to other changes that need to take place in order for cancer to develop.

Isaacs and colleagues estimated that nearly 90 per cent of men living in Sweden carry one or more of the 5 SNPs, and therefore have an elevated risk of prostate cancer compared to men who have none.

Swedes tend to marry other Swedes, and their populations are relatively homogenous compared to many western nations. Thus there is a smaller genetic variation in the Swedish populations, making them ideal subjects for studies like this, where genetic factors play a large part in assessing the relative risk of a disease. The health system in Sweden also makes it easier to get hold of well managed registries of patient data, said the researchers.

Another co-author of the study, Dr Henrik Gronberg, professor of epidemiology at the Karolinska Institute, said that Swedes also suffer from higher grade prostate and other cancers. Compared to American caucasians, deaths among Swedish caucasians are some 10 to 20 per cent higher, he said.

“Cumulative Association of Five Genetic Variants with Prostate Cancer.”
Zheng, S. Lilly, Sun, Jielin, Wiklund, Fredrik, Smith, Shelly, Stattin, Par, Li, Ge, Adami, Hans-Olov, Hsu, Fang-Chi, Zhu, Yi, Balter, Katarina, Kader, A. Karim, Turner, Aubrey R., Liu, Wennuan, Bleecker, Eugene R., Meyers, Deborah A., Duggan, David, Carpten, John D., Chang, Bao-Li, Isaacs, William B., Xu, Jianfeng, Gronberg, Henrik.
N Engl J Med 2008 0: NEJMoa075819.
Published online January 16, 2008 (10.1056/NEJMoa075819)

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Sources: NEJM press release, journal article, American Association for Cancer Research fact sheet on SNPs.

Written by: Catharine Paddock