Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

U-M scientists say fused genes trigger the development of prostate cancer

28.10.2005


Discovery could lead to prostate-cancer-specific diagnostic test and more effective treatment



Scientists at the University of Michigan Medical School, in collaboration with researchers at Harvard’s Brigham and Women’s Hospital, have discovered a recurring pattern of scrambled chromosomes and abnormal gene activity that occurs only in prostate cancer.

In a paper being published in the Oct. 28 issue of Science, the research team indicates that these chromosomal rearrangements induce specific genes to merge, creating what scientists call a gene fusion. U-M researchers detected the unique molecular signature of these fused genes in the majority of prostate cancer tissue samples they analyzed, but found no evidence of gene fusion in benign prostate tissue or in prostate tissue with non-cancerous changes.


"The data in our study provides tantalizing evidence that gene fusion is the causative agent - the initiating event - in prostate cancer," says Arul M. Chinnaiyan, M.D., Ph.D., the S.P. Hicks Collegiate Professor of Pathology in the U-M Medical School, who directed the study. "It’s what drives the aberrant over-expression of cancer-causing genes and is the first step in the progression of tissue changes leading to prostate cancer."

Because this particular gene fusion occurs only in prostate cancer, a diagnostic test to detect, in blood or urine, the fused genes or their protein products would be specific for prostate cancer and far more accurate than current screening tests, according to Chinnaiyan. And if scientists could find a way to block the gene, it could be the basis for a new, effective treatment for prostate cancer.

According to the American Cancer Society, more American men will be diagnosed with prostate cancer this year than with any other type of cancer. The American Cancer Society estimates that, in 2005, 232,000 men in the United States will be diagnosed with prostate cancer and 30,350 men will die from the disease. It is the second most common cause of cancer-related deaths in men.

"Studying gene alterations in prostate cancer is difficult, and as a result there has never been a clear identification of recurrent, non-random genetic rearrangements," says Jacob Kagan, Ph.D., program director for the Cancer Biomarkers Research Group at the National Cancer Institute, a sponsor of the research study. "This finding is an important advance, because it suggests that similar mechanisms may be involved in other epithelial cancers, such as breast, lung and colon."

The abnormal gene fusion associated with prostate cancer occurs when one of two genes, ERG or ETV1, merges with a prostate-specific gene called TMPRSS2. ERG and ETV1 are members of the ETS family of transcription factors, which are known to be involved in the development of a bone cancer called Ewing’s sarcoma, and other types of cancer.

While rearrangements in chromosomes and fused genes have been detected in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma, this is the first time they have been found in a common solid tumor like prostate cancer, which develops in epithelial cells lining the prostate gland.

"This is a paradigm shift for all epithelial tumors - such as cancers of the lung, breast, colon, ovary, liver and prostate - which are the most common types of cancer and account for most deaths due to cancer," says Chinnaiyan, who directs the Bioinformatics Core at the U-M Comprehensive Cancer Center. "We knew gene rearrangements were involved in hematologic malignancies and sarcomas. But finding this recurrent chromosomal rearrangement in prostate cancer suggests that other common epithelial cancers have their own recurrent chromosomal rearrangements. We just haven’t found them yet."

A bioinformatics analysis method called Cancer Outlier Profile Analysis (COPA) developed by Scott A. Tomlins and Daniel R. Rhodes, U-M graduate students working in Chinnaiyan’s laboratory, made it possible for the research team to detect extremely high expression levels of outlier genes, including ERG and ETV1, in 132 gene expression microarray datasets and six independent prostate cancer profiling studies.

U-M scientists also used laboratory analysis techniques and gene sequencing to detect gene fusions between TMPRSS2 and ERG or ETV1 in prostate cancer tissue samples. "Of 22 cases with high expression of ERG or ETV1, 91 percent showed evidence of a fusion with TMPRSS2," said Scott Tomlins, a U-M graduate student in pathology and first author of the Science paper. "Our results indicate that more than half of all prostate cancer cases have one of these two fusions."

Tomlins adds that TMPRSS2 may fuse to other members of the ETS family, in addition to ERG and ETV1. "We think there are more fusions. We just haven’t found them yet," he says. "To develop a diagnostic test with full sensitivity, it will be important to identify all the molecular fusions, and we are working on that now."

"We are especially excited by the profound implications these findings have for the treatment of prostate cancer," Chinnaiyan says. "It will allow us to categorize prostate tumors by molecular sub-type, which could help determine the most effective treatment for each patient."

"This collaborative effort has yielded an important molecular biomarker that will help us better detect prostate cancer and ultimately help clinicians determine the risk of dying from the disease," says Mark A. Rubin, M.D., chief of urologic pathology at Brigham and Women’s Hospital, who is also an associate professor of pathology at Harvard Medical School and a co-author on the paper.

In future research, U-M scientists hope to identify small molecule inhibitors for the genes involved in prostate cancer, which would be analogous to Gleevec - a drug designed to target the BCR-ABL gene fusion that causes chronic myelogenous leukemia. The U-M research team plans additional studies to verify that gene fusion induces prostate cancer in research animals. And they will search for recurrent chromosomal rearrangements in other common epithelial cancers.

The research was supported by the National Cancer Institute’s Early Detection Research Network, the National Cancer Institute’s Specialized Program of Research Excellence in Prostate Cancer, the American Cancer Society, the Department of Defense, the U-M Comprehensive Cancer Center Bioinformatics Core and the U-M Medical Scientist Training Program.

The University of Michigan has filed a provisional patent application on this research technology.

Additional research collaborators from U-M include research fellows Saravana Dhanasekaran, Ph.D., Rohit Mehra, M.D., and Sooryanarayana Varambally, Ph.D.; Xuhong Cao, research associate; James Montie, M.D., the Valassis Professor of Urological Oncology; Rajal B.Shah, M.D., clinical assistant professor of pathology; and Kenneth J. Pienta, M.D., professor of internal medicine and urology. Additional collaborators from Brigham and Women’s Hospital include Sven Perner, Xiao-Wei Sun, Joelle Tchinda and Charles Lee. Rainer Kuefer from the University of Ulm in Germany also collaborated in the research study.

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu
http://www.mcancer.org

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>