SEATTLE—With prostate cancer on the rise in countries acrossthe globe, and physicians struggling to diagnose and effectively treat some ofthe more aggressive forms of the disease, a team of researchers at the FredHutchinson 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, andlittle is understood about the most aggressive forms of the disease. Theprimary risk factors are age and family history. No single gene is responsiblefor prostate cancer; in fact, many different genes have been implicated. Butuntil now, the genetic composition of prostate cancer tumors have been poorlydefined, says Akash Kumar, a graduate student in genome sciences and anM.D.-Ph.D. candidate at UW.
"The technology just hasn't been there," Kumar, who was thelead author on the paper, explains. "DNA sequencing has only recently come to apoint where we can interrogate all protein-encoding genes efficiently."
That's why the researchers turned to exome sequencing, whichoffers cost reductions and greater efficiency than whole-genome sequencingbecause it zeroes in on just 1 percent of the human genome—or the exome, ahighly 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 proteincoding, but by focusing on only one portion of the genome that is coding, weare able to focus more on these tumors."
In a study published Sept. 26 in the Proceedings of theNational Academy of Sciences Early Edition,FHCRC/UW team describes how it used exome sequencing to discover a number ofrecurrent genetic mistakes that are common to advanced prostate cancer and maycontribute to disease progression. The researchers also identify severalinstances of genetic "hypermutation," a gross excess of single-letter DNA"spelling errors" that could cause the cancer to become resistant to therapiescommonly used to slow the progression of advanced prostate cancer, such asandrogen-blocking drugs and surgical castration.
FHCRC researchers contributed to the concepts underlying thestudy and confirmed the identified mutations using alternate technologies,while their colleagues at UW provided key tissue samples and a majority of theexome sequencing and analysis.
To catalog protein-altering mutations that may drive thedevelopment of prostate cancers and their progression to metastatic diseasesystematically, the researchers performed whole-exome sequencing of 23 prostatecancers derived from 16 different lethal metastatic tumors and three high-gradeprimary carcinomas.
On average, each tumor genome contained about 200 novelnon-synonymous variants, of which the vast majority was specific to individualcarcinomas. A subset of genes was recurrently altered across tumors derivedfrom different individuals, including TP53, DLK2, GPC6 and SDF4.
The researchers' most interesting finding was theirdiscovery of three aggressive tumor types that had 10 times the number ofmutations compared to the other advanced prostate cancers they studied, Kumarsays.
"That was very surprising to us," he says, but notes thatthe study did not provide answers about the cause of the hypermutated tumors.Rather, the frequency of the mutations suggests the tumors might evolve veryrapidly to develop resistance to therapies, he adds.
According to the team's paper, their results also suggestthat "increasingly deep catalogs of human germline variation may challenge thenecessity of sequencing matched tumor normal pairs."
The study, says Kumar, lays the foundation for the eventualdevelopment of screening tests for early detection of drug targets to slow orhalt cancer growth.
"This study involved a relatively small sample size," hesays. "We are now conducting a similar study on a larger set of samples usingan even more targeted approach, looking at those genes that have beenidentified as potentially important. Any study that helps shed light on an aggressivedisease is well received. We are excited by the response we have received sofar 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, anassociate professor of Genome Sciences at UW and an affiliate member of theFHCRC's Human Biology Division.
Funding for this study was provided by the U.S. Departmentof Defense, the National Institutes of Health, the Richard M. Lucas Foundation,the Prostate Cancer Foundation and the Pacific Northwest Prostate CancerSpecialized Programs of Research Excellence.
