Shattered chromosomes give clue to childhood medulloblastoma and neuroblastoma

Last year, the surprising discovery of chromothripsis– literally translated as “chromosome shattering” – revealed an entirely novel way for the DNA in cancer cells to get messed up, and opened the door to new ideas about how tumours develop and progress.

Unlike the slow and steady march of DNA damage that characterises many tumours – like the accumulation of typos in a recipe book – researchers found that some cells were experiencing a single episode of genetic vandalism on a grand scale. Their ‘recipe book’ was being torn to pieces and glued back together in a random and haphazard way.

Scientists around the world have been delving further into this phenomenon over the past year. And chromothripsis has now been found in a small but significant percentage of different types of cancer, notably leukaemias and multiple myeloma.

Now two recent papers from international research groups show that chromothripsis may be an important event during the development of two types of childhood cancer – medulloblastoma (the most common type of brain tumour in children), and neuroblastoma, which affects nerve tissue outside the brain.

Chromothripsis, Li Fraumeni syndrome and medulloblastoma

The first of these two papers comes from an international team led by German researchers – funded by German Cancer Aid, the BMBF, the European Commission and other organisations – and published in the highly-respected journal Cell. It’s based on results from a pilot study carried out as part of the International Cancer Genome Consortium, which regular readers may be familiar with.

The researchers used hi-tech DNA sequencing techniques to ‘read’ the entire genome of a tumour sample taken from a patient with a condition called Li Fraumeni Syndrome, who had subsequently developed medulloblastoma.

Li Fraumeni Syndrome is a rare syndrome caused by inheriting a faulty version of the TP53 gene (a.k.a. p53), and only about 400 families have ever been diagnosed. Carriers have a 25-fold increased risk of several different types of cancer, including breast, brain and bone tumours.

Detailed analysis of the patient’s tumour revealed characteristic patterns of DNA damage in the patient’s cancer cells, compared to their healthy cells. These looked suspiciously like the ‘shattered and patched’ signature of chromothripsis.

To find out whether this was just a one-off case, the scientists then looked at tumour samples from 98 other medulloblastoma patients. Thirteen of these had the fingerprints of chromothripsis, and eleven were of the same subtype as their original patient (known as Sonic Hedgehog medulloblastoma, named after a gene referencing a computer game character from the 1990s).

The team then looked at the entire genetic sequence in three more Sonic Hedgehog medulloblastomas from patients with Li Fraumeni syndrome. Again, the hallmarks of chromothripsis were plain to see. What’s more, the genetic chaos caused by chromosome shattering had particularly affected ‘driver’ genes known to be involved in the development of the Sonic Hedgehog form of the disease.

The researchers think that carrying a faulty copy of TP53 significantly increases the chances of chromosome shattering. In turn, this raises the chances of developing the Sonic Hedgehog form of medulloblastoma, although exactly how this all happens isn’t clear.

What does this mean for patients?

These findings have two implications for patients and their families. Firstly, it suggests that it’s worth investigating whether children with Sonic Hedgehog medulloblastoma and their relatives should be tested to see if they have Li Fraumeni syndrome – in which case they might benefit from regular cancer screening.

The researchers also suggest that doctors may need to take extra care when devising treatment for children with this particular form of medulloblastoma, as carrying a faulty copy of TP53 can increase the likelihood of the tumour developing resistance to therapy. They point out that having a faulty TP53 gene can also raise the risk of treatment such as radiotherapy causing a secondary cancer later in life.

Sonic Hedgehog medulloblastoma is the most unpredictable form of this particular cancer, making it difficult for doctors to know how an individual patient will respond to treatment, or how likely they are to survive. These results are a significant step towards stripping away this mystery, and will doubtless help researchers develop improvements for patients in the future.

The neuroblastoma connection

The second paper comes from a team in the Netherlands – funded by the Villa Joep Foundation, the Netherlands Cancer Foundation and others – and was published in Nature in February.

These researchers looked at tumour samples taken from 87 children with neuroblastoma – a cancer that develops in nerve tissue outside the brain, most commonly in the adrenal glands. Again, the team used the latest technology to ‘read’ the entire genome of each of these tumours, and compared it with DNA from healthy cells from the same patients.

As well as providing an insight into the genetic faults that may be driving these cancers, ten tumours bore the characteristic fingerprints of chromothripsis.

Intriguingly, these fingerprints were only found in the most aggressive forms of neuroblastoma (known as stage 3 and 4), which are less likely to respond to treatment and have a worse outlook.

The discovery of chromothripsis in aggressive neuroblastoma will take a while to translate into benefits for patients, but other aspects of this research do have direct relevance for treating the disease.

The researchers discovered that several of the more aggressive tumours had faults in genes controlling nerve cell growth, which probably contribute to the development of the cancer by preventing nerve cells from growing healthily. Importantly, this can be overcome using a drug called retinoic acid (based on vitamin A), which is already used as a long-term treatment for some types of neuroblastoma.

So perhaps this kind of genetic information might help predict which tumours might be more likely to respond to retinoic acid treatment. And it will also help scientists develop future treatments for neuroblastoma to overcome this defect in nerve cell growth.

Where next?

Both papers provide vital insights that will hopefully be translated into benefits for children with these types of cancer as soon as possible. They also open a fascinating window onto the genetic chaos reigning inside individual tumours – something that has only become possible thanks to recent leaps in genomic technology.

There’s still a lot to find out about chromothripsis, such as exactly how chromosomes get shattered in the first place and how they are stitched back together again. But this research is a big step in the right direction – although advances in treatment can never come soon enough for patients and their families, it’s exciting to see the ‘genetic revolution’ starting to bear fruit in this way.

Kat

References

Rausch T, et al. (2012). Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell, 148 (1-2), 59-71 PMID: 22265402

Molenaar JJ, et al. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature PMID: 22367537