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Prostate clues in the genome

Genetic association studies, involving tens of thousands of men with prostate cancer, have identified about 30 gene variants that are mildly associated with the disease (Nat. Genet. 41, 1116–1121; 2009).

Deadly division: Two prostate cancer cells Credit: SPL / Photo Researchers, Inc.

But whereas these discoveries may eventually help point to biochemical pathways underlying cancer, they don't do much for predicting risk. That's because most of the variants are common, present in at least 5% of the population. Carrying one only slightly increases an individual's risk.

In 2005, Arul Chinnaiyan found a genetic signature that could be more useful. Analyzing genes that are overexpressed in prostate cancer tissue, he found that more than half of tumors harbor an abnormal chromosomal fusion between the TMPRSS2 gene and that encoding a specific transcription factor, ERG (Science 310, 644–648; 2005).

“It's our belief that certainly this fusion is an initiating event in prostate cancer,” says Chinnaiyan, director of the University of Michigan's Center for Translational Pathology. “Our goal is to develop it into some sort of relatively economical screening test.”

But the fusion marker and the variants pinpointed in the genetic association studies suffer from one of the same problems as PSA: they reveal men who have, or are likely to develop, any kind of prostate cancer, rather than only the aggressive forms.

At Johns Hopkins, Bill Isaacs' group is now screening men who have aggressive tumors and comparing their genetic makeup to men who have nonthreatening cancers. He says he's found the first common risk variant that confers risk of the aggressive kind but has not yet published the data.

Meanwhile, in October, engineers and biochemists from the University of Toronto unveiled a crude prototype of a $10, handheld silicon chip device that screens urine samples for TMPRSS2 fusions in 30 to 60 minutes (ACS Nano. 3, 3207–3213; 2009). The device could be adapted to screen for multiple genetic or protein biomarkers, says lead investigator Ted Sargent. “The entire premise of our approach is that there will not be a silver bullet.”

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Hughes, V. Prostate clues in the genome. Nat Med 15, 1342 (2009).

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