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Research increases grasp of prostate cancer predisposition

Keck School scientists offer new clues about disease

With concerns about the effectiveness of prostate cancer diagnosis still in question, newly published research led by Keck School of Medicine of USC scientists reveals clues that could lead to more precise understanding of the disease and ultimately may lead to fewer false diagnoses of the disease.

The research, published on Jan. 30 in PLOS Genetics, finds that regulatory regions called enhancers implicate prostate cancer risk in 77 regions of the human genome previously associated with prostate cancer. The research combined data mining through bioinformatics and lab work to put hypotheses to the test, said Gerhard Coetzee, professor of urology, preventive medicine and molecular microbiology and immunology at the Keck School.

“We culled publicly available databases that demarcate areas in the human genome that potentially regulate gene expression and put it together with existing data on single nucleotide polymorphisms (SNPs) risk available through several recent Genome-Wide Association Studies,” said Coetzee, who is corresponding author on the research. “Bioinformatically, we raised the hypotheses and then went to the lab to test them as proof of principle, and with two strong hypotheses [at two locations in our genome], we could show how the SNPs likely affect gene expression.”

The discovery brings researchers a step closer to finding the gene, or combination of genes, that may be involved in the genetic predisposition to prostate cancer, and more importantly, an ultimate end to incorrect diagnoses of the disease that leads to unnecessary surgical removal of the prostate.

“Most men die with the disease, not because of it,” Coetzee said. “American medicine tends to be aggressive; doctors don’t want to take chances when there isn’t enough information. We need better biomarkers to do a more informative risk analysis. Surgical removal of the prostate can drastically affect the quality of life of many men, resulting, in some cases, in incontinence and/or impotence. It’s not trivial.”

‘These two groups speak different languages’

The database search was conducted using a software tool called FunciSNP (pronounced “funky snip”), developed by Coetzee’s son Simon Coetzee and Houtan Noushmehr, both in the Department of Genetics at the University of Sao Paulo in Brazil. The tool creates functional annotations of SNPs, which are common DNA sequence variations among human beings.

The research is significant, not only because of the discovery but because of the collaboration between basic molecular biologists and genetic epidemiologists, Coetzee said, noting that USC is “blazing the trail” in such cooperative research.

“These two groups speak different languages,” he said. “As a hardcore molecular biologist working in the lab, I saw genetic epidemiology as ‘soft’ science, but I now see it as complicated and disciplined. We are each masters of our own domains and very comfortable working with each other. It’s a good group.”

Coetzee also gave credit for the paper’s success to first author Dennis Hazelett, research associate in Coetzee’s lab, who wrote the paper after doing the end-analyses.

The study was funded by National Institutes of Health (grant numbers R01CA136924 and U19CA148537).

USC researchers involved in the study included Peggy Farnham, Brian Henderson, Christopher Haiman, Wendy Cozen, Wange Lu, Suhn Kyong Rhie, graduate student Malaina Gaddis, technician Chunli Yan and Daniel Lakeland. Also participating were Rosalind Eeles of the Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust, United Kingdom, Douglas Easton of the Center for Cancer Genetic Epidemiology at the University of Cambridge and Zsofia Kote-Jarai of the Institute of Cancer Research, United Kingdom.

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Research increases grasp of prostate cancer predisposition

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