Overlooked DNA shuffling drives deadly paediatric brain tumour

Crystal structure of Myc and Max in complex with DNA. Credit: Mark AbsturZ/Wikipedia

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 . To tackle the question, Jan Korbel's group at EMBL and collaborators at DKFZ tried to identify new 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 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 -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.

More information: Northcott, P.A., Lee, C., Zichner, T. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Published online in Nature on 22 June 2014. DOI: 10.1038/nature13379

add to favorites email to friend print save as pdf

Related Stories

Study reveals genes behind brain tumours

Oct 31, 2013

A team of researchers has pinpointed a handful of genes that could drive the formation of medulloblastoma, the most aggressive and frequent form of brain tumour found in children.

Insights into genetics of cleft lip

May 27, 2014

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, have identified how a specific stretch of DNA controls far-off genes to influence the formation of the face. The study, published ...

ASH: Mutation in GFI1B causes gray platelet syndrome

Dec 10, 2013

(HealthDay)—A mutation has been identified in the gene encoding the transcription factor growth factor independent 1B (GFI1B), which causes gray platelet syndrome, according to a study published online ...

Recommended for you

Immune checkpoint inhibitors may work in brain cancers

Nov 21, 2014

New evidence that immune checkpoint inhibitors may work in glioblastoma and brain metastases was presented today by Dr Anna Sophie Berghoff at the ESMO Symposium on Immuno-Oncology 2014 in Geneva, Switzerland.

New model of follow up for breast cancer patients

Nov 21, 2014

Public health researchers from the University of Adelaide have evaluated international breast cancer guidelines, finding that there is potential to improve surveillance of breast cancer survivors from both a patient and health ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
not rated yet Jun 23, 2014
Re: Atheist blogger, PZ Myers and chromosomal rearrangements

This biology teacher has done more to prevent others from accurately representing biologically based cause and effect that might lead to disease prevention that most people I have encountered.

He has frequently attacked anyone who suggests or shows that the involvement of chromosomal rearrangements is the important thing to consider in the context of cell type differentiation either in health or disease. Instead, he wants others to continue to believe that mutation-initiated natural selection is the cause of evolution and biodiversity.

Watch how he manages to let his idiot minions persuade other idiot minions that anyone who challenges his pseudoscientific nonsense is a "crank."

http://freethough...-page-1/

Then see: http://www.scienc...14001869 for a model of chromosomal rearrangements in speciation.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.