Summary: Based on a large scale meta analysis, researchers report striking differences between children’s high grade gliomas, so much so that they could be split into 10 different subtypes based on different characteristics. The findings have important implications for developing new and individualized treatments.
Source: Institute of Cancer Research.
Scientists have found that deadly childhood brain tumours are actually 10 different diseases that should each be diagnosed and treated based on their specific genetic faults.
The major new study has important implications for treatment, since personalising care for each type of brain tumour is likely to be much more effective than grouping them all together as one.
A team at The Institute of Cancer Research, London, found stark differences among children’s ‘high grade’ brain tumours, or gliomas, and that they could be split into at least 10 different cancers.
Some types should be far more treatable than others using drugs under development or already on the market.
The study, published today in Cancer Cell, is the world’s largest of these aggressive childhood brain cancers and should lead to more accurate diagnostic tests to ensure each child receives the best possible treatment.
Targeting tumours with existing drugs
Many of the children had mutations in their tumours that can be targeted by existing drugs approved for adult cancers, demonstrating the benefit of testing children for genetic mutations in their tumours at the point of diagnosis.
Researchers gathered genetic data from 910 cases from 20 previously published analyses and 157 new cases, from children or young adults up to the age of 30 with high-grade glioblastoma or diffuse intrinsic pontine glioma (DIPG).
Although rare, these are the biggest cause of cancer-related death in people under 19 years of age because survival rates are so poor – children with these tumours are only expected to live an average of 9-15 months.
It is therefore vital to find out more about their biology, what makes them so deadly, and how they might be treated.
The tumours could be split into different subtypes based on different characteristics, such as age at diagnosis, area of the brain, the number of genetic mutations and – crucially – errors in key genes that drive the disease.
Tumours driven by a single genetic error
One of the striking findings from the study was that while some children’s tumours were driven by a single genetic error in which two genes were fused together, others had tens of thousands of genetic errors – among the highest number of mutations in any human cancer.
Tumours with mutations in a gene called BRAF were found to be much less aggressive than some of the other cancers, and actually shouldn’t be classified as ‘high grade’ at all. These tumours could be susceptible to several adult cancer drugs that target BRAF mutations.
Scientists at the ICR, a research institute and charity, found mutations in common cancer genes such as PDGFRA, KIT, MYCN, EGFR, CDK6, and genes involved in DNA repair – all of which can be targeted by existing drugs.
They also uncovered numerous new potential therapeutic targets within each subtype, such as the gene TOP3A – a gene involved in DNA replication – in tumours with a specific type of histone mutations called H3.3K27M.
Three of the subtypes were distinguished by the presence or absence of different mutations in genes that produce histones – proteins that DNA is wrapped around to pack it tightly into cells. Histones are also involved in turning off and on certain genes – a role that can be very important in cancer.
Although there are currently no drugs that can target histone mutations, there are some in development and the presence or absence of these mutations gave clues about how aggressive the cancer is, and could point to future approaches to treatment.
The data produced by this study is now considered the definitive dataset on these cancers, and will be made available on a public data portal so the research community can use it to develop new tests and treatments.
“We are working to better understand the complexities specific to childhood cancers. This knowledge is enabling us to improve treatments. This important study is a vital step forward”
Study leader Professor Chris Jones, Professor of Childhood Brain Tumour Biology at the ICR, said:
“Our study uncovered a wealth of new information about children’s brain cancers. We found that tumours that have historically been lumped together under one diagnosis are in fact comprised of many, remarkably different, diseases.
“Treating cancer based only on what we see down the microscope simply isn’t good enough any more. We need to start thinking about these as completely different cancers and diagnosing and treating them based on their genetic faults.
“It’s exciting that several types look like they could be clearly treatable using either existing drugs on the market or other treatments under development.
“We worked with colleagues across the world to gather enough data on these rare cancers to understand better what makes them so aggressive, and what mutations occur that might make them susceptible to different treatments.”
Professor Paul Workman, Chief Executive of the ICR, said:
“A diagnosis with one of these high-grade brain tumours in children is very bad news and devastating for families. We desperately needed to understand the biology of the diseases better if we are ever to find ways of treating them effectively. This important study is a vital step forward.
“We really need to get much better at making modern, targeted cancer treatments available for children, which means improving access to genetic testing and changing regulations so more drugs get tested in paediatric clinical trials.”
Raising awareness of childhood brain tumours
Jo Williams lost her son Lucas after he was diagnosed with a brain tumour in May 2015. Jo and her husband Andrew set up the charity Lucas’ Legacy in their son’s name, to fund research into, and raise awareness of, childhood brain tumours. Jo said:
“We lost Lucas, our beautiful only child, in August 2015 following a short battle with a brain tumour. Before this Lucas had never been ill, or had a day off school. After a roller coaster of desperate hope and extreme despair, Lucas died at home – 11 weeks and one day after first becoming ill, and just four weeks away from his seventh birthday.
“After Lucas died, we were so sad to find out how little is invested in developing treatments for children with brain cancer. The standard treatment regimes that children receive for high-grade brain tumours are brutal, and Lucas went through so much. He fought so hard, but he deserved so much more, to have better treatments in his brave and courageous fight against this devastating illness.
“Professor Jones and his team are working hard to understand children’s brain tumours better and to develop personalised treatments for children like Lucas, kinder treatments that will give them a better chance of survival.
“We are still so shocked that this happened to our seemingly healthy six-year-old boy. Lucas was a really kind, funny, clever, sporty boy and the centre of our world. We know that he would have grown up to be something really special. We know that he would have changed the world for the better. We still hope he will.”
Funding: The research was funded by The Institute of Cancer Research (ICR) itself along with many different charitable funders – Cancer Research UK, CRIS Cancer Foundation, Abbie’s Army, The Lyla Nsouli Foundation, Christopher’s Smile and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Hospital Children’s Charity and Children with Cancer UK.
Source: Claire Hastings – Institute of Cancer Research
Image Source: NeuroscienceNews.com image is adapted from the ICR news release.
Original Research: Full open access research for “Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma” by Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, Sara Temelso, Sergey Popov, Valeria Molinari, Pichai Raman, Angela J. Waanders, Harry J. Han, Saumya Gupta, Lynley Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry C. Mandeville, Leslie R. Bridges, Andrew J. Martin, Safa Al-Sarraj, Christopher Chandler, Ho-Keung Ng, Xingang Li, Kun Mu, Saoussen Trabelsi, Dorra H’mida-Ben Brahim, Alexei N. Kisljakov, Dmitry M. Konovalov, Andrew S. Moore, Angel Montero Carcaboso, Mariona Sunol, Carmen de Torres, Ofelia Cruz, Jaume Mora, Ludmila I. Shats, João N. Stavale, Lucas T. Bidinotto, Rui M. Reis, Natacha Entz-Werle, Michael Farrell, Jane Cryan, Darach Crimmins, John Caird, Jane Pears, Michelle Monje, Marie-Anne Debily, David Castel, Jacques Grill, Cynthia Hawkins, Hamid Nikbakht, Nada Jabado, Suzanne J. Baker, Stefan M. Pfister, David T.W. Jones, Maryam Fouladi, André O. von Bueren, Michael Baudis, Adam Resnick, and Chris Jones in Cancer Cell. Published online September 28 2017 doi:10.1016/j.ccell.2017.08.017
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma
•Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups
•Somatic coding mutations per tumor range from none to among the highest seen in human cancer
•Histone mutations co-segregate with distinct alterations and downstream pathways
•H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
“Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma” by Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, Sara Temelso, Sergey Popov, Valeria Molinari, Pichai Raman, Angela J. Waanders, Harry J. Han, Saumya Gupta, Lynley Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry C. Mandeville, Leslie R. Bridges, Andrew J. Martin, Safa Al-Sarraj, Christopher Chandler, Ho-Keung Ng, Xingang Li, Kun Mu, Saoussen Trabelsi, Dorra H’mida-Ben Brahim, Alexei N. Kisljakov, Dmitry M. Konovalov, Andrew S. Moore, Angel Montero Carcaboso, Mariona Sunol, Carmen de Torres, Ofelia Cruz, Jaume Mora, Ludmila I. Shats, João N. Stavale, Lucas T. Bidinotto, Rui M. Reis, Natacha Entz-Werle, Michael Farrell, Jane Cryan, Darach Crimmins, John Caird, Jane Pears, Michelle Monje, Marie-Anne Debily, David Castel, Jacques Grill, Cynthia Hawkins, Hamid Nikbakht, Nada Jabado, Suzanne J. Baker, Stefan M. Pfister, David T.W. Jones, Maryam Fouladi, André O. von Bueren, Michael Baudis, Adam Resnick, and Chris Jones in Cancer Cell. Published online September 28 2017 doi:10.1016/j.ccell.2017.08.017