FHCRC, UW team provide first comprehensive assessment of DNA errors involved in advanced prostate cancer
by Amy Swinderman  |  Email the author


SEATTLE—With prostate cancer on the rise in countries across the globe, and physicians struggling to diagnose and effectively treat some of the more aggressive forms of the disease, a team of researchers at the Fred Hutchinson Cancer Research Center (FHCRC) and the University of Washington (UW) are hoping their new study assessing every gene in the genome of advanced, lethal prostate cancer will offer new insights into the progression of it.  
The specific causes of prostate cancer remain unknown, and little is understood about the most aggressive forms of the disease. The primary risk factors are age and family history. No single gene is responsible for prostate cancer; in fact, many different genes have been implicated. But until now, the genetic composition of prostate cancer tumors have been poorly defined, says Akash Kumar, a graduate student in genome sciences and an M.D.-Ph.D. candidate at UW.  
"The technology just hasn't been there," Kumar, who was the lead author on the paper, explains. "DNA sequencing has only recently come to a point where we can interrogate all protein-encoding genes efficiently."  
That's why the researchers turned to exome sequencing, which offers cost reductions and greater efficiency than whole-genome sequencing because it zeroes in on just 1 percent of the human genome—or the exome, a highly functional region that harbors the majority of disease-causing mutations.  
"Prostate cancer is hard to isolate and study," Kumar says. "Previously, sequencing whole genomes has been a good way to assay protein coding, but by focusing on only one portion of the genome that is coding, we are able to focus more on these tumors."  
In a study published Sept. 26 in the Proceedings of the National Academy of Sciences Early Edition, FHCRC/UW team describes how it used exome sequencing to discover a number of recurrent genetic mistakes that are common to advanced prostate cancer and may contribute to disease progression. The researchers also identify several instances of genetic "hypermutation," a gross excess of single-letter DNA "spelling errors" that could cause the cancer to become resistant to therapies commonly used to slow the progression of advanced prostate cancer, such as androgen-blocking drugs and surgical castration.  
FHCRC researchers contributed to the concepts underlying the study and confirmed the identified mutations using alternate technologies, while their colleagues at UW provided key tissue samples and a majority of the exome sequencing and analysis.  
To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, the researchers performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas.  
On average, each tumor genome contained about 200 novel non-synonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6 and SDF4.  
The researchers' most interesting finding was their discovery of three aggressive tumor types that had 10 times the number of mutations compared to the other advanced prostate cancers they studied, Kumar says.
"That was very surprising to us," he says, but notes that the study did not provide answers about the cause of the hypermutated tumors. Rather, the frequency of the mutations suggests the tumors might evolve very rapidly to develop resistance to therapies, he adds.
According to the team's paper, their results also suggest that "increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor normal pairs."  
The study, says Kumar, lays the foundation for the eventual development of screening tests for early detection of drug targets to slow or halt cancer growth.
"This study involved a relatively small sample size," he says. "We are now conducting a similar study on a larger set of samples using an even more targeted approach, looking at those genes that have been identified as potentially important. Any study that helps shed light on an aggressive disease is well received. We are excited by the response we have received so far and look forward to seeing where the study goes."  
Corresponding authors on the paper were Dr. Peter S. Nelson, a member of the FHCRC's Human Biology Division, and Dr. Jay Shendure, an associate professor of Genome Sciences at UW and an affiliate member of the FHCRC's Human Biology Division.
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