Changes to chromosomes impact how children’s brain tumours respond to treatment

Cancer

The Armed Forces Institute of Pathology, US

“Brain tumours are amongst the most difficult-to-treat cancers,” explains Professor Steve Clifford, Chair of Molecular Paediatric Oncology at the University of Newcastle. “It’s especially heartbreaking when they affect children.”

Medulloblastoma is a children’s brain cancer that develops in the back of the brain, in an area called the cerebellum.

This type of brain cancer can grow quickly and spread to other parts of the brain and spine.

Every year in the UK, around 55 children are diagnosed with medulloblastoma, and there is a pressing need for new treatments.

Now, led by Professor Clifford, Cancer Research UK scientists based at Newcastle University Centre for Cancer have identified changes in chromosomes that explain why some of these childhood tumours respond better to treatment.

The researchers hope that this new knowledge will help doctors to better understand the chances of survival when a child is diagnosed with medulloblastoma. The results could also help scientists design more precise and effective treatments for the condition.

Knowing when, how and why these chromosome changes occur will allow us to better treat medulloblastoma, especially those types of medulloblastoma which can be less responsive to existing treatments.

Professor Steve Clifford, Chair of Molecular Paediatric Oncology at the University of Newcastle

No two tumours look the same

Professor Steve Clifford, Chair of Molecular Paediatric Oncology at the University of Newcastle 

Professor Steve Clifford

Every cell in our body has more than 2 metres of DNA tightly wrapped up into little packages called chromosomes. DNA is made up of genes which contain all the instructions that tell a cell what to do.

Children’s cancer often sees changes, or mutations, to DNA, including whole chromosomal changes, such as aneuploidy.

This is one of the biggest challenges with treating medulloblastoma. Because of the complexity of the tumour’s genetic makeup, no two tumours are the same.

“Even within a medulloblastoma tumour, cells can have big differences in the quantity and structure of chromosomes, which affects which parts of the tumour we can target for treatment,” says Clifford.

“Knowing when, how and why these chromosome changes occur will allow us to better treat medulloblastoma, especially those types of medulloblastoma which can be less responsive to existing treatments.”

Decoding the tumours

Medulloblastoma is currently classified into different subtypes depending on how a tumour looks down a microscope, based on its molecular features. There are 4 broad groups of medulloblastoma tumour:

  • Wingless medulloblastoma (MBWNT)
  • Sonic hedgehog medulloblastoma (MBSHH)
  • Group 3 medulloblastoma (MBGrp3)
  • Group 4 medulloblastoma (MBGrp4).

MBWNT tumours are more likely to respond to treatment compared to the other subtypes, but the exact reasons why there is a such a variation in treatment response is not yet well understood.

So Clifford and his team analysed 14 tumours across the 4 subtypes of medulloblastoma. “The sequencing tools available to us now allow us to see, in much greater detail, the driving forces behind the different types of medulloblastoma at the single-cell level,” says Clifford.

They isolated large numbers of cell nuclei from the tumour, where the genetic code (chromosomes) of each individual cell are stored, and decoded them one by one to find out how cells within the tumour differed.

The team discovered that subtypes of medulloblastoma with the highest survival rates typically had tumours with genetically identical cancer cells. On the other hand, tumours with 3 or 4 genetically different types of cancer cell were only found in subtypes of medulloblastoma with the lowest survival rates.

Digging into the details

When the team examined the tumours with 3 or 4 variations of cancer cells in them, they found that the cells had gained and lost chromosomes over time, giving them different sets of genes, which could help tumours evade treatment.

The scientists made another remarkable discovery when they investigated the unique mutations that are currently used to diagnose subtypes of medulloblastoma. No matter how many other chromosomal changes had taken place, every cell they looked at within individual tumours had kept identical copies of these identifying mutations.

This finding suggests that these ‘driver’ mutations are required for medulloblastoma tumours to start and keep growing, and could reduce the need for multiple biopsies to assess the tumour’s composition.

The more we learn about how these tumours grow, the better we can detect and treat them. This new knowledge about the evolutionary paths of different types of medulloblastoma will pave the way for further research and could ultimately lead to new treatments.

Dr Laura Danielson, Children and Young People’s Research Lead at Cancer Research UK

While this study is a great step in the right direction, further research is required to find out exactly which genes are duplicated or lost when these genetically different types of cell emerge. But scientists hope that this important information will enable them to better understand the patient’s chances of survival when they are diagnosed with medulloblastoma.

“We are now at the stage where we can clearly see what changes cause medulloblastoma to emerge in the first place, and the paths it can go down that determine how aggressive it is likely to be,” says Clifford. “We hope that these findings will give doctors and scientists the information they need to develop more precise and effective treatments for the different types of medulloblastoma.”

Lilly

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