Featured Research

from universities, journals, and other organizations

Researchers map genome of advanced, lethal prostate cancers and discover 'hypermutation'

Date:
September 27, 2011
Source:
Fred Hutchinson Cancer Research Center
Summary:
Researchers have conducted the first comprehensive assessment of every gene in the genome of advanced, lethal prostate cancer. Until now, the genetic composition of such tumors had been poorly defined.

A team of researchers at Fred Hutchinson Cancer Research Center and the University of Washington has conducted the first comprehensive assessment of every gene in the genome of advanced, lethal prostate cancer. Until now, the genetic composition of such tumors had been poorly defined.

In the process, they have discovered a number of potential key drivers -- recurrent genetic mistakes -- common to advanced prostate cancer that may contribute to disease progression. The researchers also have identified 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.

Corresponding authors Peter S. Nelson, M.D., a member of the Hutchinson Center's Human Biology Division, and Jay Shendure, M.D., Ph.D., an associate professor of Genome Sciences at UW and an affiliate member of the Hutchinson Center's Human Biology Division, and colleagues report their findings Sept. 26 in the Proceedings of the National Academy of Sciences Early Edition. The lead author of the paper was Akash Kumar, a graduate student in Genome Sciences and an M.D.-Ph.D. candidate at UW.

"The most interesting finding to come out of our DNA sequencing project was the discovery of three aggressive tumor types that had 10 times the number of mutations compared to the other advanced prostate cancers we studied," Nelson said. "That was very surprising and unusual. We don't know the cause of these hypermutated tumors, but the frequency of the mutations suggests these tumors might evolve very rapidly to develop resistance to therapies."

The discovery of these genetic mutations should provide clues that illuminate why some prostate cancers are lethal, and potentially could be used to develop screening tests for early detection or drug targets to slow or halt cancer growth, Nelson said.

"The mutations underlying the progression of prostate cancer to an advanced state have been understudied to date," Shendure said. "Although further work is certainly necessary, our hope is that identifying the genes in which these mutations occur will facilitate biological insights and the development of new therapeutic strategies."

For the study, the researchers determined the mutational status of 23 aggressive and lethal, drug-resistant human prostate cancers, including those that had metastasized, or spread, beyond their primary site of origin and those that had not. They used a technology called exome sequencing to survey the mutational landscape. This method is more efficient and cost-effective than whole-genome sequencing because it zeroes in on just 1 percent of the human genome -- the exome -- a highly functional region that harbors the majority of disease-causing mutations.

In aggressive tumors, the researchers identified a number of genes with recurrent germline (inheritable) or somatic (noninheritable) mutations, including variants in TP53, a gene that encodes tumor protein p53, which normally functions as a tumor suppressor; and GPC6, a gene that encodes glypican-6, which regulates cell growth and division. They also found recurrent mutations in several genes whose mechanisms in prostate cancer development are not yet well understood, as well as thousands of individual, or "personal," mutations unique to individual tumors.

The researchers also found that of nearly 90 mutations associated with tumors that are resistant to testosterone suppression -- a common treatment for advanced prostate cancer -- each tumor studied had at least one mutation in the Wnt signaling pathway, a network of proteins known to play a variety of important roles in embryonic development and cancer, among other things.

Nelson and researchers at the Hutchinson Center contributed to the concepts underlying the study and confirmed the identified mutations using alternate technologies. Shendure and colleagues at the UW provided key tissue samples and a majority of the exome sequencing and analysis, among other contributions.

Funding for the research came from the U.S. Department of Defense, National Institutes of Health, Richard M. Lucas Foundation, Prostate Cancer Foundation and Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence.


Story Source:

The above story is based on materials provided by Fred Hutchinson Cancer Research Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Akash Kumar, Thomas A. White, Alexandra P. MacKenzie, Nigel Clegg, Choli Lee, Ruth F. Dumpit, Ilsa Coleman, Sarah B. Ng, Stephen J. Salipante, Mark J. Rieder, Deborah A. Nickerson, Eva Corey, Paul H. Lange, Colm Morrissey, Robert L. Vessella, Peter S. Nelson, and Jay Shendure. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. PNAS, September 26, 2011 DOI: 10.1073/pnas.1108745108

Cite This Page:

Fred Hutchinson Cancer Research Center. "Researchers map genome of advanced, lethal prostate cancers and discover 'hypermutation'." ScienceDaily. ScienceDaily, 27 September 2011. <www.sciencedaily.com/releases/2011/09/110926151731.htm>.
Fred Hutchinson Cancer Research Center. (2011, September 27). Researchers map genome of advanced, lethal prostate cancers and discover 'hypermutation'. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2011/09/110926151731.htm
Fred Hutchinson Cancer Research Center. "Researchers map genome of advanced, lethal prostate cancers and discover 'hypermutation'." ScienceDaily. www.sciencedaily.com/releases/2011/09/110926151731.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

Reuters - US Online Video (Aug. 30, 2014) California lawmakers pass a bill requiring universities to adopt "affirmative consent" language in their definitions of consensual sex, part of a nationwide drive to curb sexual assault on campuses. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
New Drug Could Reduce Cardiovascular Deaths

New Drug Could Reduce Cardiovascular Deaths

Newsy (Aug. 30, 2014) The new drug from Novartis could reduce cardiovascular deaths by 20 percent compared to other similar drugs. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins