Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Telomeres: 2 genes linked to why they stretch in cancer cells

01.07.2011
Scientists at Johns Hopkins have provided more clues to one of the least understood phenomena in some cancers: why the "ends caps" of cellular DNA, called telomeres, lengthen instead of shorten.

In a study published online June 30 in Science Express, the Johns Hopkins researchers say they have identified two genes that, when defective, may cause these telomere elongations.

Telomeres contain repeated sequences of DNA that, in normal cells, shorten each time a cell divides. Without telomeres, the cell division-related shortening could snip off a cell's genes and disrupt key cell functions. Most cancer cells, naturally prone to divide rapidly, use high amounts of an enzyme called telomerase to keep their telomeres intact. Yet, some cancer cells are known to maintain their telomere length without help from telomerase.

With no increased production of telomerase, scientists were left to wonder how cancer cells managed to maintain their telomeres, a phenomenon known as "alternative lengthening of telomeres."

"Finding the genes responsible for alternative lengthening of telomeres is the first step in understanding this process and provides opportunities to develop new drug therapies," says Nickolas Papadopoulos, Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center and director of translational genetics at Johns Hopkins' Ludwig Center.

The first clues to the genes linked to the process came from a study led by Papadopoulos that mapped the genome of pancreatic neuroendocrine tumors, published in the Jan. 20 issue of Science Express. The most prevalent gene alterations in those tumors occurred in genes that include ATRX and DAXX. Proteins made by these genes interact with specific portions of DNA to alter how its chemical letters are read. ATRX and DAXX had also been linked to similar functions in the telomere region, says Alan Meeker, Ph.D., assistant professor of pathology, urology and oncology at Johns Hopkins.

Following a hunch, Meeker and his colleagues took a closer look at the two genes and their specific role in telomere lengthening. With tissue samples from 41 patients with pancreatic neuroendocrine tumors collected during the genome mapping project, the scientists found characteristic signatures of alternative telomere lengthening in 25 of them. Fluorescent dyes targeted specifically to telomeres showed "huge aggregates of telomere DNA" in the 25 samples, with each fluorescent spot holding about 100 times more telomere DNA than normal cells, according to Meeker.

Nineteen of the 25 samples that glowed positive for alternative telomere lengthening had either ATRX or DAXX mutations. Six of those 25 samples did not contain ATRX or DAXX mutations, but the tumor cells showed no expression of these two genes. The remaining 16 samples with no alternative lengthening lacked mutations and had adequate ATRX and DAXX expression.

"We saw a 100 percent correlation between abnormalities in ATRX and DAXX and alternative lengthening of telomeres," says Meeker.

Among 439 other samples of tumors tested by Meeker, Papadopoulos and colleagues, ATRX mutations were found in several brain cancer types, including pediatric and adult glioblastoma samples provided by Hai Yan, M.D., Ph.D., and Darell Bigner, M.D., Ph.D., of Duke University.

Meeker and colleagues tested the telomeres status in glioblastoma samples with tissue available for the assay. All eight glioblastoma tissue samples with ATRX mutations showed the characteristic bright glow of their telomeres, indicative of alternative lengthening, and lack of ATRX expression.

Although the Johns Hopkins team does not yet have an explanation for how the genes do their lengthening work in cancer, Meeker speculates that the mutations alter the way that telomere DNA is packaged, exposing those areas to instability.

Papadopoulos' genome mapping studies showed that patients with pancreatic neuroendocrine tumors containing ATRX/DAXX mutations had better survival than those without the mutations.

"If the correlation holds up, we could use alternative lengthening of telomeres and ATRX/DAXX mutations as a method of determining a patient's prognosis in addition to developing treatments that target these genes," says Meeker.

Funding for the study was provided by the Caring for Carcinoid Foundation, a nonprofit foundation that funds research on carcinoid cancer, pancreatic neuroendocrine cancer, and related neuroendocrine cancers, the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer, National Institutes of Health, the Sol Goldman Pancreatic Cancer Research Center, the American Cancer Society, the Pediatric Brain Tumor Foundation Institute, the Duke Comprehensive Cancer Center Core, the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, and the Department of Defense Breast Cancer Research Program.

Co-authors of the research include Christopher M Heaphy, Roeland F de Wilde, Yuchen Jiao, Alison P Klein, Barish H Edil, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban, Anirban Maitra, Chetan Bettegowda, Fausto J Rodriguez, Charles G Eberhart, and Sachidanand Hebbar from Johns Hopkins; Chanjuan Shi from Vanderbilt University; Johan A Offerhaus from the University Medical Center Utrecht, the Netherlands; Roger McLendon, B. Ahmed Rasheed, Yiping He, Hai Yan, and Darell D. Bigner from Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie from the University of Sao Paulo, Brazil.

Photo of fluorescent telomeres in pancreatic neuroendocrine tumor cells available upon request.

Vanessa Wasta | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Nesting aids make agricultural fields attractive for bees
20.07.2017 | Julius-Maximilians-Universität Würzburg

nachricht The Kitchen Sponge – Breeding Ground for Germs
20.07.2017 | Hochschule Furtwangen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

Leipzig HTP-Forum discusses "hydrothermal processes" as a key technology for a biobased economy

12.07.2017 | Event News

 
Latest News

Researchers create new technique for manipulating polarization of terahertz radiation

20.07.2017 | Information Technology

High-tech sensing illuminates concrete stress testing

20.07.2017 | Materials Sciences

First direct observation and measurement of ultra-fast moving vortices in superconductors

20.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>