Featured Research

from universities, journals, and other organizations

Periodic bursts of genetic mutations drive prostate cancer

Date:
April 25, 2013
Source:
Weill Cornell Medical College
Summary:
Cancer is typically thought to develop after genes gradually mutate over time, finally overwhelming the ability of a cell to control growth. But a new closer look at genomes in prostate cancer by an international team of researchers reveals that, in fact, genetic mutations occur in abrupt, periodic bursts, causing complex, large scale reshuffling of DNA driving the development of prostate cancer.

Cancer is typically thought to develop after genes gradually mutate over time, finally overwhelming the ability of a cell to control growth. But a new closer look at genomes in prostate cancer by an international team of researchers reveals that, in fact, genetic mutations occur in abrupt, periodic bursts, causing complex, large scale reshuffling of DNA driving the development of prostate cancer.

In the April 25 issue of Cell, the scientists, led by researchers from Weill Cornell Medical College, the Broad Institute, Dana-Farber Cancer Institute and the University of Trento in Italy, dub this process "punctuated cancer evolution," akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the researchers named these periodic disruptions in cancer cells that lead to complex genome restructuring "chromoplexy."

"We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer," says the study's co-lead investigator Dr. Mark Rubin, who is director of the recently-established Institute for Precision Medicine at Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future," says Dr. Rubin, also the Homer T. Hirst III Professor of Oncology, professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell. "Our findings represent a new way to think about cancer genomics as well as treatment in prostate and, potentially, other cancers."

The discovery of "chromoplexy" came after the research team worked collaboratively to sequence the entire genomes of 57 prostate tumors and compare those findings to sequences in matched normal tissue.

Co-lead investigator Dr. Levi Garraway, of the Broad Institute and Dana-Farber Cancer Institute, and his collaborators then tracked how genetic alterations accumulated during cancer development and progression. They used advanced computer techniques to identify periodic bursts of genetic derangements.

"We have, for the first time, mapped the genetic landscape of prostate cancer as it changes over time," says Dr. Garraway, a senior associate member of the Broad Institute and associate professor at the Dana-Farber Cancer Institute and Harvard Medical School. "The complex genomic restructuring we discovered, which occurs at discrete times during tumor development, is a unique and important model of carcinogenesis which likely has relevance for other tumor types."

Co-senior author Dr. Francesca Demichelis, assistant professor at the Centre for Integrative Biology at the University of Trento who also serves as adjunct assistant professor of computational biomedicine at Weill Cornell, worked with her collaborators to understand how widespread the DNA mutations and alterations seen in the tumors were across the cancer samples, and what that might mean in terms of cancer progression and, potentially, treatment. "Information about what alterations are common, and which aren't, will most likely help guide us in terms of cancer drug use and patient response," says Dr. Demichelis.

The researchers also report that future targeted cancer therapy may depend on identifying complex sets of genetic mutations and rearrangements in each patient.

"Every cancer patient may have individual patterns of genetic dysfunction that will need to be understood in order to provide precise treatment. Multiple drugs may be needed to shut down these genetic derangements," says Dr. Rubin. "Providing those tests now on every patient isn't possible, but our study suggests that punctuated cancer evolution may occur to provide a subset of genes that offer a selective advantage for tumor growth. If that is true, we may be able to zero in on a limited number of genetic drivers responsible for an individual's prostate cancer."

Astonishing Degree of Genetic Alterations

The collaborators have been working together for a number of years exploring and mapping the prostate cancer genome. They believe that structural genomic alterations are key to prostate cancer development and progression, and their approach has been to model those changes and tease apart the significance of those alterations.

This study sequenced 57 prostate cancer genomes as well as the entire genomes of matched normal tissue. Researchers revealed an astonishing number of genetic alterations in the prostate cancer cells -- 356,136 base-pair mutations and 5,596 rearrangements that were absent from normal DNA. Of those rearrangements, 113 were validated by re-sequencing and other methods.

"We saw wholesale rearrangements of chromosomes -- the cutting up and retying of chromosomes -- mutations we have never seen on that scale," Dr. Garraway says. "Our research teams then charted a path of oncogenic events that appeared to drive prostate cancer."

Using advanced computer techniques that modeled the genomic rearrangements and copy number alterations, the scientists at the Broad Institute inferred that the chromosomal disarray in a typical tumor might accumulate over a handful of discrete events during tumor development.

"The rearrangement of chromosomes can coordinately affect specific genes, which provides a selective advantage for cancer growth," according to Dr. Garraway.

"Chromoplexy is a common process by which geographically-distant genomic regions may be disrupted at once, in a coordinated fashion," says Dr. Rubin. "The unifying feature is that these alterations seem to occur in a sequential, punctuated pattern which is designed to eliminate cancer-fighting genes. This suggests that genes that are active at the end of these events may drive progression of the cancer."

"This study represents a wonderful example of a team science that embraces multidisciplinary competencies," says Dr. Demichelis.

The study required the development of special computational tools to go beyond the pure detection -- presence or absence -- of any particular aberration, and to quantify the dosage of the mutation; meaning, how many tumor cells have that specific mutation in the patient's tumor.

"The approach developed in my laboratory takes advantage of the genetic information of each individual and classifies every aberration as homogenous or heterogeneous across the tumor cells," Dr. Demichelis says. "This classification allows us then to chart the order in which mutations occur and to learn how far the tumor is in its progression. It suggests to us that patients with heterogeneous aberrations may not respond as effectively to a drug as patients with homogenous alterations."

"The punctuated changes we see occur in a single cycle of cell growth, and we believe this leads to tumor cells that have a growth advantage," says Dr. Rubin. "This new model of cancer growth tells us that cells gain an advantage mutating multiple genes simultaneously as opposed to gradually."

"These are exciting findings in a field of prostate cancer genomics that our research team's collaboration has redefined. We have made a lot of progress, but we have much more work to do," adds Dr. Rubin.


Story Source:

The above story is based on materials provided by Weill Cornell Medical College. Note: Materials may be edited for content and length.


Journal Reference:

  1. SylvanC. Baca, Davide Prandi, MichaelS. Lawrence, JuanMiguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, TheresaY. MacDonald, Mahmoud Ghandi, Eliezer VanAllen, GregoryV. Kryukov, Andrea Sboner, Jean-Philippe Theurillat, T.David Soong, Elizabeth Nickerson, Daniel Auclair, Ashutosh Tewari, Himisha Beltran, RobertC. Onofrio, Gunther Boysen, Candace Guiducci, ChristopherE. Barbieri, Kristian Cibulskis, Andrey Sivachenko, ScottL. Carter, Gordon Saksena, Douglas Voet, AlexH. Ramos, Wendy Winckler, Michelle Cipicchio, Kristin Ardlie, PhilipW. Kantoff, MichaelF. Berger, StaceyB. Gabriel, ToddR. Golub, Matthew Meyerson, EricS. Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, MarkA. Rubin, LeviA. Garraway. Punctuated Evolution of Prostate Cancer Genomes. Cell, 2013; 153 (3): 666 DOI: 10.1016/j.cell.2013.03.021

Cite This Page:

Weill Cornell Medical College. "Periodic bursts of genetic mutations drive prostate cancer." ScienceDaily. ScienceDaily, 25 April 2013. <www.sciencedaily.com/releases/2013/04/130425132628.htm>.
Weill Cornell Medical College. (2013, April 25). Periodic bursts of genetic mutations drive prostate cancer. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2013/04/130425132628.htm
Weill Cornell Medical College. "Periodic bursts of genetic mutations drive prostate cancer." ScienceDaily. www.sciencedaily.com/releases/2013/04/130425132628.htm (accessed October 1, 2014).

Share This



More Health & Medicine News

Wednesday, October 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Newsy (Sep. 30, 2014) The CDC says a new case of Ebola has not been reported in Nigeria for more than 21 days, leading to hopes the outbreak might be nearing its end. Video provided by Newsy
Powered by NewsLook.com
UN Ebola Mission Head: Immediate Action Is Crucial

UN Ebola Mission Head: Immediate Action Is Crucial

AFP (Sep. 30, 2014) The newly appointed head of the United Nations Mission for Ebola Emergency Response (UNMEER), Anthony Banbury, outlines operations to tackle the virus. Duration: 00:39 Video provided by AFP
Powered by NewsLook.com
CDC Confirms First Case of Ebola in US

CDC Confirms First Case of Ebola in US

AP (Sep. 30, 2014) The CDC has confirmed the first diagnosed case of Ebola in the United States. The patient is being treated at a Dallas hospital after traveling earlier this month from Liberia. (Sept. 30) Video provided by AP
Powered by NewsLook.com
New Breast Cancer Drug Extends Lives In Clinical Trial

New Breast Cancer Drug Extends Lives In Clinical Trial

Newsy (Sep. 30, 2014) In a clinical trial, breast cancer patients lived an average of 15 months longer when they received new drug Perjeta along with Herceptin. 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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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