Diagnostics & Imaging Week Correspondent

LONDON – The reasons some men develop prostate cancer, and why some prostate cancers are more aggressive than others, are likely to become clearer over the next few years, with the discovery of a clutch of genetic variants that raise a man’s risk of the disease.

Study of the variants – and, ultimately, of the genes they affect – is likely to clarify the biological basis of the disease and will almost certainly lead to new therapeutic strategies and population-based screening programs.

Three research teams recently published their findings from genome-wide association studies of men with prostate cancer in Nature Genetics.

Doug Easton, director of the Genetic Epidemiology Unit of Cancer Research UK at the University of Cambridge (Cambridge, UK), and a co-author of one of the studies, told Diagnostics & Imaging Week’s sister publication BioWorld International: “Prostate cancer is a very poorly understood disease. We have suspected for a long time that, unlike in breast cancer and bowel cancer, where there are some single genes that confer high risk of disease, the genetic component of prostate cancer is made up of many genes acting together. We can now, for the first time, see what the genetic architecture of prostate cancer is.”

The findings are expected to enable researchers to explore the potential lifestyle or environmental factors that influence the development of prostate cancer, he added, and will certainly make it possible to identify people who are an increased risk of developing the disease.

Easton and his colleagues report their study in a paper in Nature Genetics titled: “Multiple newly identified loci associated with prostate cancer susceptibility.”

The team, funded by Cancer Research UK, carried out a genome-wide association study. This involved comparing small variations in the genomes of about 2,000 men with prostate cancer with those of about 2,000 men without prostate cancer. The comparison allowed the researchers to identify a small number of regions of the genome that were highly significantly associated with prostate cancer.

In the next stage of the study, the scientists concentrated on these regions and looked for variations in them in the genomes of a further 3,000 men with prostate cancer and 3,000 controls.

“There were five previously known regions and we found all of these,” Easton said. “In addition, we found another seven regions containing variants that are each associated with an increased risk of prostate cancer, varying from 1.1-fold to 1.6-fold. These are common variants, so their combined effect is going to be quite substantial.”

None of the seven regions were previously known to be related to cancer predisposition. Some have obvious candidate genes within them.

One of the most important of these genes is MSMB. This codes for a protein that is secreted by the prostate, and hence could be measured in blood or urine. Studies to examine the expression levels of the protein encoded by this gene in men with prostate cancer are already under way.

“The MSMB protein has the potential to become an important marker of prostate cancer, like prostate specific antigen,” said Easton.

One of the genes identified as important by this study, KLK2, encodes the protein known as prostate specific antigen (PSA), which is the basis for existing screening tests for prostate cancer.

Another, called KLK3, encodes a protein called HK2, which has been previously associated with prostate cancer. Prostate tumours are known to secret it. Again, Easton suggested, this protein has the potential to become the basis for a screening test.

Other genes may open up new therapeutic avenues for exploration. The gene LKTK2, for example, encodes a kinase and is therefore involved in signal transduction. “As well as helping us to understand the biology of the disease, this protein appears to be a potentially attractive therapeutic target,” Easton said.

There is a further region of interest on the X chromosome, and several that are present in what appear to be “gene deserts.”

An American team also reported identifying several loci that are linked with prostate cancer. Gilles Thomas, of the National Cancer Institute in Bethesda, MD, and colleagues published a paper in the same issue of Nature Genetics titled: “Multiple loci identified in a genome-wide association study of prostate cancer.”

Writing in Nature Genetics, the authors conclude: “Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.”

The third study, also published in Nature Genetics, is from deCODE Genetics (Reykjavik, Iceland).

Julius Gudmundsson and colleagues report two variants associated with prostate cancer in their paper, titled: “Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer”.

deCODE also reported the launch of a test for common single nucleotide polymorphisms (SNPs) in the human genome that the company has associated with increased risk of prostate cancer. The test detects 6 previously known SNPs plus the two just published by deCODE in Nature Genetics.

Ros Eeles, one of the authors of the Cancer Research UK study, said: “The results we have found ... have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature. Research needs to be done to identify how such profiling helps to tailor prostate cancer screening regimes, for example, we need to determine how often PSA needs to be done and whether and when biopsy is indicated.”