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Gene shuffling deals dangerous genetic outcome in childhood brain tumour
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A search for large-scale DNA rearrangements has revealed a surprising genetic phenomenon associated with the deadly paediatric brain tumour, Group 3 medulloblastoma. The study from a research team in 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 the journal Nature. The results reveal that a ‘DNA shuffling’ event places the genes growth factor independent 1 transcription repressor (GFI1) or growth factor independent 1b transcription repressor (GFI1b) in proximity with enhancer elements that dramatically increase their expression.

Group 3 medulloblastoma is the most common paediatric brain tumour and has a higher rate of metastasis and a poorer prognosis than other types of this tumour. It has different subtypes and currently available treatments only cure a subset of patients and are associated with significant morbidity in the long-term. Therefore, increased insight into the mechanisms of this disease are vital in moving towards new therapies. Up until now, only the oncogene MYC had been firmly established as playing an important part in Group 3 medulloblastoma but this couldn’t explain many aspects of the disease. In the current study, the research team endeavoured to identify other genes involved. To do this they exploited the large known number of medulloblastoma sequences.

The team took a different approach to that usually used in identifying genetic changes in solid tumours. Instead of looking at individual gene changes, they concentrated on large-scale rearrangements in the areas between the genes. DNA from different patients was revealed to harbour a multitude of changes, among them inversions, deletions and duplications and importantly complex ‘DNA shuffling’ events. These events had one outcome in common; they placed GFI1b in close proximity to gene enhancer elements which are drivers of gene transcription, so that the expression of the GFI1b gene was now switched on in situations and cells where it would normally be switched off. While GFI1b was not affected in all patients, in many where it wasn’t a related gene called GFI1, which is on a different chromosome, was similarly shuffled so that it was in proximity to an enhancer. The research team suggest that it is these shuffling events that drive formation of the tumours. Study first author Dr Paul Northcott commented: “Nobody has seen such a process in solid cancers before…although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”

To further elucidate the role of GFI1b and GFI in medulloblastoma, the team engineered neural stem cells to express either GFI1b or GFI1 along with MYC and introduced these stem cells into the brains of healthy mice. These mice went on to develop aggressive, metastatic brain tumours very similar to human Group 3 medulloblastoma. These mice represent a genetic model for Group 3 medulloblastoma that can now be used to test potential therapies based on the study findings. For example, an existing class of drugs called bromodomain inhibitors can be used to target enhancer elements. The study has also created a potential diagnostic tool as GPI1b and GPI1 are not normally expressed in the brain.

The mice studies also left a puzzle for the research team to solve. For tumours to develop, the mice had to have MYC switched on as well as activation of GFI1B or GFI1. However, the groups established a statistical association between GFI1 and MYC but not between GFI1b and MYC. Further studies are addressing this puzzle. Senior author Dr Jan Korbel concluded: “What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes.”

Sources

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.

Press release: European Molecular Biology Laboratory; available from http://www.embl.de/aboutus/communication...eidelberg/ [Accessed 23 June 2014]
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Gene shuffling deals dangerous genetic outcome in childhood brain tumour00