̽��ֱ�� of Cambridge - Great Ormond Street Hospital Children’s Charity

Cutting-edge genomic test can improve care of children with cancer

Anonymous — Tue, 02 Jul 2024 09:00:37 +0000

̽��ֱ��study, published on 2 July in Nature Medicine, is the first time that the impact of using whole genome sequencing in current NHS practice has been assessed. It was led by researchers at the ̽��ֱ�� of Cambridge, Cambridge ̽��ֱ�� Hospitals NHS Trust, Wellcome Sanger Institute and Great Ormond Street Hospital.

̽��ֱ��team analysed the use of routine genome sequencing, through the NHS Genomic Medicine Service, at Cambridge ̽��ֱ�� Hospitals, where such tests are given to all children with solid tumours, and at Great Ormond Street Hospital, which provides the test for childhood leukaemia.

̽��ֱ��researchers found that cancer sequencing gave new insights that improved the immediate clinical care of seven per cent of children, while also providing all the benefits of current standard tests.

Furthermore, in 29 per cent of cases, genome sequencing provided additional information that helped clinicians better understand the tumours of individual children and informed future management. For example, uncovering unexpected mutations that increase future cancer risk leading to preventative measures being taken, such as regular screening.

Overall, whole genome sequencing provides additional, relevant data, about childhood cancer that is useful for informing practice. ̽��ֱ��results also show that it can reduce the number of tests required, and therefore, researchers suggest it should be provided to all children impacted by cancer.

Whole genome sequencing (WGS) is a single test that provides a complete readout of the entire genetic code of the tumour and identifies every single cancer-causing mutation. Comparatively, traditional standard-of-care tests only look at tiny regions of the cancer genome, and therefore many more tests are often required per child.

Professor Sam Behjati, senior author from the Wellcome Sanger Institute, Cambridge ̽��ֱ�� Hospitals, and the ̽��ֱ�� of Cambridge: “Whole genome sequencing provides the gold standard, most comprehensive and cutting edge view of cancer. What was once a research tool that the Sanger Institute started exploring over a decade ago, has now become a clinical test that I can offer to my patients. This is a powerful example of the genomic data revolution of healthcare that enables us to provide better, individualised care for children with cancer.”

NHS England is one of the few health services in the world that has a national initiative, through the Genomic Medicine Service, offering universal genome sequencing to every child with suspected cancer. However, due to multiple barriers and a lack of evidence from real-time practice supporting its use, whole cancer genome sequencing is not yet widespread practice.

̽��ֱ��latest study looked at 281 children with suspected cancer across the two units. ̽��ֱ��team analysed the clinical and diagnostic information across these units and assessed how genome sequencing affected the care of children with cancer.

They found that WGS changed the clinical management in seven per cent of cases, improving care for 20 children, by providing information that is not possible to acquire from standard of care tests.

Additionally, WGS faithfully reproduced every one of the 738 standard of care tests utilised in these 281 cases, suggesting that a single WGS test could replace the multiple tests that the NHS currently uses if this is shown to be economically viable.

WGS provides a detailed insight into rare cancers, for example, by revealing novel variants of cancer. ̽��ֱ��widespread use of genome sequencing will enable clinicians to access these insights for individual patients while simultaneously building a powerful shared genomic resource for research into new treatment targets, possible prevention strategies, and the origins of cancer.

Dr Jack Bartram, senior author from Great Ormond Street Hospital NHS Foundation Trust and the North Thames Genomic Medicine Service, said: “Childhood cancer treatment is mostly guided by genetic features of the tumour, and therefore an in-depth genetic understanding of cancer is crucial in guiding our practice. Our research shows that whole genome sequencing delivers tangible benefits above existing tests, providing better care for our patients. We hope this research really highlights why whole genome sequencing should be delivered as part of routine clinical care to all children with suspected cancer.”

Professor Behjati at the Department of Paediatrics, ̽��ֱ�� of Cambridge, and is a Fellow of Corpus Christi College, Cambridge.

This research was supported in part by Wellcome, the Pessoa de Araujo family and the National Institute for Health and Care Research.

Reference
A Hodder, S Leiter, J Kennedy, et al. Benefits for children with suspected cancer from routine whole genome sequencing. Nature Medicine; 2 July 2024; DOI: 10.1038/s41591-024-03056-w

Adapted from a press release from Wellcome Sanger Institute

Whole genome sequencing has improved clinical care of some children with cancer in England by informing individual patient care. Research published today supports the efforts to provide genome sequencing to all children with cancer and shows how it can improve the management of care in real-time, providing more benefits than all current tests combined.

This is a powerful example of the genomic data revolution of healthcare that enables us to provide better, individualised care for children with cancer

Sam Behjati

FatCamera (Getty Images)

Boy Battling With Cancer

Eddie’s story

When he was six-years old, Eddie began to have regular low-grade fevers that seemed to affect him a lot. Even though early tests came back normal, the fevers became more frequent and his Mum, Harri, noticed that on one or two occasions he seemed out of breath while doing small things like reading a book. A chest x-ray revealed a huge mass on Eddie’s chest, and he was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). Eddie was immediately transferred to Great Ormond Street Hospital (GOSH) to begin treatment.

“I know it sounds like a cliché, but you really don’t think it will ever happen to your child. It felt like our world fell out from under us. During those first few weeks I remember wondering if this was it, I was taking so many photos of us together and wondering if it could be the last,” said Harri, Eddie's mum.

Eddie was put onto a treatment plan that included eight months of intense chemotherapy, followed by two and a half years of maintenance treatment. As part of his treatment at GOSH Eddie’s family were also offered WGS to identify any cancer-causing changes.

“When we were offered whole genome sequencing, we didn’t even hesitate. I wanted to have all the information, I wanted to have some peace of mind for the future and know that Eddie was having the right care throughout. I also wanted to make sure that Eddie’s brother, Leo, wasn’t any more likely to get T-ALL because Eddie had,” said Harri.

On his seventh birthday, Eddie’s family received the call to say he was in remission. Now, at nine years-old Eddie is nearing the end of his maintenance treatment and is doing well.

“We are trying to live each day, and this experience has really changed our outlook on life. We always try to take the positive from every situation. Words can’t explain what Eddie has been through this past three years but he has come out the other side as a sensitive, confident, and smart young man. He is mature beyond his years and he has been involved in everything, including decisions about his treatment. To say we are proud, doesn’t even come close to how we truly feel about him,” said Harri.

Their personal experience of WGS was so important on their journey that they provided support for this research.

Harri added: “I always say that having a child with a cancer diagnosis feels like you’ve been standing on a trap door all these years without knowing. Then after the diagnosis, you are in freefall. And even when things are stable again, you are constantly aware that the trap door is still there and there is a possibility it could open again at any time. Having access to whole genome sequencing gave us some sense of reassurance, it could have informed us about targeted treatments and gave us some insight into future risk. We wanted to support something that had the potential to have a real impact on treatment and outcomes so when we heard about this research project and its potential, it was very exciting that we could be a small part of it. It helped us turn something so devastating into something positive and we just hope that this research helps.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Children with rare genetic disorders more likely to be diagnosed with developmental, behavioural and mental health problems

cjb250 — Wed, 03 Aug 2022 22:30:47 +0000

With the advent of rapid whole genome sequencing, children presenting with an intellectual disability or developmental delay are recommended to have their DNA sequenced to identify the underlying genetic cause.

To capitalise on this recent NHS development, researchers at the ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and Cardiff ̽��ֱ�� established IMAGINE ID, a national UK cohort study that aims to discover how genetic changes affect children and young people’s behaviour, in order to inform better care of families and children now and in the future.

Writing in ̽��ֱ��Lancet Psychiatry today, the researchers have published the results of an analysis of data from almost 2,800 young people with rare genomic variants – changes to their DNA – that are associated with intellectual disability.

Professor Lucy Raymond from the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability. What we’ve found from parents is that these children are extremely likely to develop other neurodevelopmental or mental health conditions, which can present additional challenges both to the children and their families.”

All the participants were aged between four and 19 years. Just under three-quarters (74%) had an intellectual disability caused by a duplication or deletion of sections of DNA – a so-called copy number variant (CNV). ̽��ֱ��remaining young people had a disability caused by a single ‘spelling error’ in their DNA – a change in the A, C, G or T nucleotides – referred to as a single nucleotide variant (SNV).

Compared to the English national population, children in the study were almost 30 times as likely to have been diagnosed as autistic. In the general population, 1.2% of people are diagnosed with the condition compared to 36% of the study participants. Similarly, 22% of the study population were diagnosed with ADHD, compared to 1.6% of the general population, meaning that they were more than 13 times more likely to have the condition.

Around one in eight children (12%) had been diagnosed with oppositional defiant disorder, in which children are uncooperative, defiant, and hostile toward others – a rate 4.4 times higher than in the general population.

One in ten (11%) had an anxiety disorder, a 1.5 times increased risk. Rates of childhood depression were significantly lower, at just 0.4% compared with 2.1% of the general population, but this may increase over the next few years as some mental health disorders do not start until later adolescence or early adult life. Almost all of the children (94%) were reported to have at least one significant physical health problem, including disturbed sleep (65%), motor or movement disorders (64%) or seizures (30%).

Dr Jeanne Wolstencroft from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “Routine genomic testing now allows parents to understand the genetic cause of intellectual disabilities in an increasing number of children but, because so many of these conditions are rare, we still lack information on the impact this has on their children’s future mental health.

“We already know that intellectual disabilities tend to be associated with an increased likelihood of neurodevelopmental conditions, as well as emotional and behavioural difficulties, but we found that where there is an identifiable genetic cause, the likelihood is amplified considerably. This suggests that these children should be provided with early assessment and help where appropriate.”

̽��ֱ��team has also shown for the first time that children with intellectual disability caused by a genetic variant inherited from a family member, are more likely to come from a more deprived socioeconomic background. This suggests that some parents or family members with the same variant may also have unrecognised difficulties that placed them at a social and educational disadvantage. These children were more likely to be diagnosed with a neuropsychiatric condition and were also more likely to exhibit behavioural difficulties.

Professor David Skuse from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “We hope this work helps improve the targeting of assessments and interventions to support families at the earliest opportunity. We’d like to see better training for health care providers about the wider use and utility of genetic testing. We have identified its potential value in terms of prioritising children with mental health needs for child mental health services, who are currently hugely limited in the UK.”

̽��ֱ��research was funded by the Medical Research Council (part of UK Research & Innovation) and the Medical Research Foundation. Additional support was provided by the NIHR Cambridge Biomedical Resource Centre and the NIHR GOSH BRC.

Reference
Wolstencroft, J et al. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE - ̽��ֱ��UK National Cohort Study. Lancet Psychiatry; 4 Aug 2022; DOI: 10.1016/PIIS2215-0366(22)00207-3

A major study of children with intellectual disabilities has highlighted the additional challenges that they often face, including a much-increased likelihood of being diagnosed as autistic, as well as Attention Deficit Hyperactivity Disorder (ADHD) and other mental health difficulties.

Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability

Lucy Raymond

PhotoAlto/Laurence Mouton (Getty Images)

Toddler's hands touching tree bark

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Low cost, safe and accurate test could help diagnose rare childhood cancers

cjb250 — Wed, 16 Dec 2015 00:00:11 +0000

Reported today in the British Journal of Cancer, the test could enable doctors to monitor the effectiveness of treatments without exposing patients to repeated doses of radiation.

̽��ֱ��target of the test is a type of cancer known as germ cell cancer. Germ cells are those cells in the body that go on to develop into sperm and egg cells. Germ cells can develop into tumours – both benign and malignant – particularly in the testes or ovaries, where the cells are normally found. However, occasionally germ cells can get trapped in the wrong part of the body during development and may later turn into brain tumours, for example.

̽��ֱ��five year disease-free and overall survival rates for patients with high-risk malignant germ cell tumours remains less than 50%, and so accurate diagnosis and monitoring is crucial to improving outcomes for patients. All of the current tests are expensive, and none are ideal.

̽��ֱ��most reliable diagnostic method currently in use is biopsy, where a section of the suspected tumour is extracted surgically and analysed by a pathologist. However, biopsies are prone to sampling errors and so may not be representative of the tumour as a whole. Computerised tomography (CT) scans and magnetic resonance imaging (MRI) also provide useful information but are not diagnostic and do not discriminate between benign and malignant tumours.

̽��ֱ��ideal tool for diagnosis would be a non-invasive blood test; however, currently available tests only identify around three in five malignant germ cell tumours, potentially delaying diagnosis and the ability to prioritise patients for surgery. Accurate disease monitoring with routine blood testing is not possible for two in five patients, requiring follow up CT scans with exposure to harmful radiation and an associated increased secondary cancer risk.

“Although relatively rare, childhood germ cell tumours need to be diagnosed accurately and followed up carefully to give us the best chances of treating them,” says Professor Nick Coleman from the Department of Pathology, ̽��ֱ�� of Cambridge. “At the moment, we are not good enough at diagnosing these tumours and monitoring their treatment: we need better, safer and more cost-effective tests.”

In research funded by Sparks charity, Great Ormond Street Hospital Children’s Charity and Cancer Research UK, researchers at the ̽��ֱ�� of Cambridge have developed a test for blood and cerebrospinal fluid samples that looks for a specific panel of four pieces of short genetic code known as microRNAs, which are found in greater quantities in malignant germ cell tumours. ̽��ֱ��test can distinguish malignant germ cell tumours from benign germ cell tumours and other cancers. ̽��ֱ��test can be used for diagnosis of malignant germ cell tumours in any part of the body, including the brain.

̽��ֱ��test can also be used to check the effectiveness of treatments and, as it is safe and cost-effective, allows for frequent testing to monitor for the recurrence of malignant germ cell tumours.

Dr Matthew Murray from the Department of Paediatric Haematology and Oncology, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, says: “This test, developed with Dr Emma Bell, a postdoctoral scientist in our laboratory, could be exactly what we need: it could help us diagnose malignant germ cell tumours cheaply, safely and above all, more accurately than current methods. Our next step is to confirm our findings in a large clinical trial and, if this is successful, we hope to see the test in routine use in hospitals in the near future.”

Reference
Murray, MJ, Bell E, et al. A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. British Journal of Cancer; 15 Dec 2015

A non-invasive, low cost blood test that could help doctors diagnose some types of malignant childhood tumour has been developed by researchers at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Health NHS Foundation Trust.

At the moment, we are not good enough at diagnosing these tumours and monitoring their treatment: we need better, safer and more cost-effective tests

Nick Coleman

̽��ֱ�� of Cambridge

Addenbrooke's Hospital

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes