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 Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)

nachricht CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

New Study Will Help Find the Best Locations for Thermal Power Stations in Iceland

19.01.2017 | Earth Sciences

Not of Divided Mind

19.01.2017 | Life Sciences

Molecule flash mob

19.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>