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Subset of Prostate Cancer Risk Alleles Verified In Japanese GWAS

NEW YORK (GenomeWeb News) – A new genome-wide association suggests that some — but not all — of the prostate cancer risk alleles detected in studies of European or African-American individuals are also risk variants in a Japanese population.

The team of Japanese and American investigators evaluated more than 300 Japanese men with prostate cancer and 1,000 healthy controls, testing for 23 SNPs that had been previously linked to prostate cancer risk, age of onset, or aggressiveness in other populations. In a paper appearing online this week in the Journal of the National Cancer Institute, they reported that almost a third of those SNPs also were associated with prostate cancer in the Japanese population.

"These results highlight the critical importance of considering ancestry in understanding how risk alleles influence disease and suggest that risk estimates and variants differ across populations," senior author Matthew Freedman, an oncology researcher at the Dana-Farber Cancer Institute, and his colleagues wrote. "It is important to perform studies in multiple ancestral populations so that the composite genetic architecture of prostate cancer can be rigorously addressed."

Several GWAS in individuals of European or African descent or mixed populations have linked a set of SNPs to prostate cancer risk. But the relationship between these SNPs and prostate cancer in other populations is less well characterized.

Even so, the researchers noted, the prevalence of prostate cancer in the US varies with ancestry, being more common in individuals of African-American ancestry and less common in those of Asian descent.

In an effort to determine whether previously identified risk alleles for prostate cancer show similar patterns in a Japanese population, the team evaluated DNA samples for 311 men with prostate cancer and 1,035 healthy controls collected at two Tokyo hospitals.

When the team used a Sequenom genotyping platform to assess 23 potential prostate cancer risk SNPs on ten chromosomes, they found that seven of the SNPs showed statistically significant associations with prostate cancer. Five of these were independently associated with the disease, while two were in linkage disequilibrium with independently associated SNPs.

In addition, the team found that two of these SNPs were associated with a younger age of prostate cancer onset. And when they looked at the SNPs as a group, the team found that Japanese men carrying at least six of the alleles were at roughly six times greater risk of prostate cancer risk than the men carrying two or fewer alleles — and tended to develop the disease at a younger age.

On the other hand, the team did not detect associations between any of the variant SNPs and prostate cancer aggressiveness.

The team cautioned that they may have missed some associations due to the study's sample size and/or differences in linkage disequilibrium patterns in the Japanese population. Still, they noted, by uncovering similarities and differences in genetic associations in different populations, the study is providing insights that may inform GWAS-based genetic tests for prostate cancer and other diseases.

"[G]iven the number of recently identified risk SNPs, prostate cancer risk assessment tests are being discussed and marketed," Freedman and his co-authors concluded. "Before applying those tests to men, it is important to understand ethnic differences so that the appropriate level of risk is applied to an individual."

In an accompanying online editorial in JNCI, John Ioannidis, a hygiene and epidemiology researcher at the University of Ioannina School of Medicine in Greece, agreed that some of the team's results likely do reflect underlying differences in the Japanese population compared with the populations in which the risk alleles were discovered.

"These data reinforce the notion that discovered variants in the GWAS setting are often simply population-specific markers that need far more effort to lead to functional culprits," Ioannidis wrote. "However, even functional culprits may differ across populations, and some may exist only in specific populations."

Even so, he noted that some of the findings may also be a consequence of the study's power, size, or the frequency with which the alleles being evaluated are found in the Japanese population.

Ioannidis also noted that the five SNPs that did replicate in the Japanese population appear to offer even better prostate cancer predictive ability than risk SNPs in Europeans. Still, he cautioned, prostate cancer GWAS need to be more extensively replicated in Japanese and other populations.

"Although we have found many promising markers for prostate cancer and other diseases through GWAS, and these have been replicated in similar populations, this is just the beginning," Ioannidis argued. "The findings need to be replicated again and then again validated."

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