Professor Michael Jenkinson
"This research would potentially allow clinicians to target radiotherapy for those patients with the greatest risk of meningioma regrowth, whilst withholding radiotherapy for those at low risk of recurrence."
Previous work, funded by The Brain Tumour Charity, has produced a clinical tool that predicts how likely it is that a person’s meningioma will recur. The tool allows doctors to benefit from knowledge about characteristics and behaviour of other people’s meningiomas, it then groups newly diagnosed meningiomas into ‘profiles’ that act in similar ways.
That work will be complemented by this new project to develop a liquid biopsy for clinically aggressive meningioma (CAM). Further, it will expand the profiles so that they not only detect CAMs, but predict response to radiotherapy too.
A critical part of this study will be access to tumour samples, and that's where UK's own Professor Michael Jenkinson comes in. Professor Jenkinson's role as the lead investigator on the ROAM clinical trial means that he can facilitate easy contribution of ROAM participants onto this forward-facing study.
Clinicians have seen that meningiomas generally fall into two categories, regardless of whether they are WHO grade I, II or III. The two categories are described as indolent (less aggressive) meningiomas and CAMs. Around 70% of all meningiomas are indolent and are often considered to be cured after surgery. To date, these more common tumours have been the primary focus of the work identifying DNA mutations that cause meningioma.
Using the samples from Professor Jenkinson, Dr Zadeh and Professor Aldape will be able to focus on the more aggressive CAMs in a three-pronged approach to develop clinical tools for diagnosis and to predict when radiotherapy after surgery would be the most effective.
The diagnosis tools they’re going to make are based on differences in tumour epigenetics. Epigenetic changes, such as DNA methylation and histone modification, are processes that control how often different parts of the DNA code (genes) are used. In tumours the exact genes that are turned on or off are different to the gene profiles in healthy cells.
Promising and exciting preliminary data indicate that tumour DNA can be detected in the blood of people with meningiomas and that the DNA methylation profiles detected can be used as a biomarker for more accurate diagnosis.
To test this further, the researchers will use 290 samples of plasma from people with a meningioma. These samples have clinical information available about the DNA methylation profile detected in the tumour itself, for comparison with the profile detected in the blood. The first 200 samples will be used to train an advanced machine learning algorithm, and a further 90 samples will validate that the algorithm works effectively. This innovation could mean it’s possible to diagnose a meningioma without surgery.
This section of work will be done in close collaboration with Professor Jenkinson in the UK-led ROAM clinical trial. ROAM (aka EORTC-1308) is testing whether radiotherapy after surgery is more effective than an observational approach for grade II meningiomas, those with less predictable outcomes. Our project team will determine the methylation profile of 190 tumours in the trial and compare it to the five-year outcome data of the clinical trial. They want to predict which tumours responded better to radiotherapy by the tumour’s methylation profile.
As well as DNA methylation, histone modification is a way of controlling how often the DNA code is used. Histones are the organisational structures that make sure the long strings of DNA in our cells (about three metres per cell) don’t get messy. Modifications of the histone structures can change how the DNA is organised, and therefore how it can be used.
One hundred meningiomas, made up of 70 CAMs and 30 indolent, will be analysed for histone modifications using a technique called chromatin immunoprecipitation and sequencing (ChIP-seq). This will help identify the modifications that are different between the two groups of tumour. Using these differences the researchers aim to build an advanced diagnostic tool for people with meningioma.
If successful this research will provide new biomarkers for aggressive meningiomas as well as a less invasive method to test for them. It would also identify the tumours that are more likely to respond to radiotherapy, sparing unnecessary treatments that are less likely to work.
This information would allow more appropriate decision-making to avoid overtreatment of patients who would not benefit from radiotherapy.
By the end of this study we hope to see changes in clinical practice that mean everyone with a meningioma has a more accurate diagnosis than is currently possible. This diagnosis will come with strong indications of whether early radiotherapy will be beneficial to them, personally.
We look forward to sharing the team’s achievements with you as the project progresses.
Dr Gelareh Zadeh
Dr Zadeh is the head of the Division of Surgical Oncology within the Department of Surgery, University Health Network, Canada. She also holds a scientific post at the Adult Brain Tumour Centre, University of Toronto, Princess Margaret Cancer Centre
Dr Kenneth Aldape
Dr Kenneth Aldape is the Chief of the Laboratory of Pathology at the Centre for Cancer Research, one of America’s prestigious National Institutes for Health.
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