Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer by remote-control: Overlooked DNA shuffling drives deadly paediatric brain tumour

24.06.2014

One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes.

The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.

To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour.

To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known. “We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel.

“Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.” Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. 

They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off.

And that, the researchers surmise, is what drives the tumour to form. “Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”

GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.

To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC.

When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans. These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further.

The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors.

And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too. But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on.

In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise. “What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.

Published online in Nature on 22 June 2014. DOI: 10.1038/nature13379.

For more information please visit: www.embl.org/press/2014/140622_Heidelberg.

Policy regarding use EMBL press and picture releases including photographs, graphics and videos are copyrighted by EMBL. They may be freely reprinted and distributed for non-commercial use via print, broadcast and electronic media, provided that proper attribution to authors, photographers and designers is made.

Sonia Furtado Neves EMBL Press Officer and Deputy Head of Communications Meyerhofstr. 1, 69117 Heidelberg, Germany Tel.: +49 (0)6221 387 8263 Fax: +49 (0)6221 387 8525 sonia.furtado@embl.de www.embl.org Keep up-to-date with EMBL Research News at: www.embl.org/news

Sonia Furtado Neves | EMBL Research News

Further reports about: Biology Cancer DKFZ DNA EMBL Laboratory Molecular chromosomes genes shuffling tumour tumours

More articles from Life Sciences:

nachricht Chains of nanogold – forged with atomic precision
23.09.2016 | Suomen Akatemia (Academy of Finland)

nachricht Self-assembled nanostructures hit their target
23.09.2016 | King Abdullah University of Science and Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

Im Focus: New laser joining technologies at ‘K 2016’ trade fair

Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.

K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

Using mathematical models to understand our brain

16.09.2016 | Event News

 
Latest News

Chains of nanogold – forged with atomic precision

23.09.2016 | Life Sciences

New leukemia treatment offers hope

23.09.2016 | Health and Medicine

Self-assembled nanostructures hit their target

23.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>