Tag Archive for: Genomic Medicine

Polygenic Score Catalog increases diversity and usability of genetic data

Credit: Karen Arnott/EMBL-EBI

A paper highlighting changes to the Polygenic Score (PGS) Catalog for genetic disease risk predictions for individuals of diverse genetic backgrounds has been published in leading journal Nature Genetics.

In the work, which was supported by NIHR Cambridge BRC and other funders, researchers added data from multi-ancestry and non-European populations and introduced a new software tool to make calculating PGS easier and more reproducible.

This work was undertaken as part of the Cambridge Baker Systems Genomics Initiative, a research partnership between the Baker Heart and Diabetes Institute and Cambridge University to significantly expand access big data and corresponding expertise to target approaches in disease prediction and personalised medicine.

Other collaborators involved in the work include the GWAS Catalog from the EMBL’s European Bioinformatics Institute (EMBL-EBI).

Data Science and Population Health Theme Lead Professor Mike Inouye – who is also Head of the Cambridge Baker Systems Genomics Initiative and Munz Chair of Cardiovascular Prediction and Prevention – said: “The PGS Catalog is the largest open database for polygenic scores with around 27,000 users from over 140 countries in the past year alone.

“These scores estimate an individual’s genetic predisposition to a specific trait or disease by summarising the effect of many different genetic variants across the genome.

“Polygenic scores are particularly useful for predicting complex health conditions such as heart disease, diabetes and certain cancers, where multiple genetic variants contribute to the overall risk.

“Integrating these scores into clinical practice could help scientists and clinicians understand the genetic influences on health, potentially leading to better prevention strategies and tailored treatments.”

About the PGS

The Polygenic Score (PGS) Catalog is an open-source resource created to make this genetic prediction method more accessible to the research community. It includes over 4500 scores predicting over 600 traits (including common diseases and lab measurements) and is heavily used in research and in industry with applications such as disease prediction. Launched in 2019, it has attracted 27,000 users from over 140 countries in the past year alone.

Due to lack of genetic data from populations of non-European ancestry, data in early releases of PGS Catalog mostly consisted of scores using data from individuals of European ancestry. Now more PGS have been added from studies using African, Asian, and often multi-ancestry data to develop and evaluate PGSs.

About the PGS Catalog Calculator

The PGS Catalog Calculator is a new addition to the PGS Catalog. This open-source software tool automates the process of calculating PGS, allowing users to apply polygenic scores to new genomic data, simplifying tasks such as genotype data formatting and variant matching.

The Calculator also implements methods for genetic similarity analysis and ancestry adjustment, an important step towards ensuring that calculated polygenic scores are more interpretable across populations. This could help to streamline the use of PGSs in research and clinical studies.

Baby born deaf can hear after breakthrough gene therapy

A baby girl born deaf can hear unaided for the first time, after receiving ground-breaking gene therapy when she was eleven months old at Addenbrooke’s Hospital in Cambridge.

Opal Sandy from Oxfordshire is the first patient treated in a global gene therapy trial, which shows “mind-blowing” results. She is the first British patient in the world and the youngest child to receive this type of treatment.

Opal was born completely deaf because of a rare genetic condition, auditory neuropathy, caused by the disruption of nerve impulses travelling from the inner ear to the brain.

Within four weeks of having the gene therapy infusion to her right ear, Opal responded to sound, even with the cochlear implant in her left ear switched off.

Clinicians noticed continuous improvement in Opal’s hearing in the weeks afterwards. At 24 weeks, they confirmed Opal had close to normal hearing levels for soft sounds, such as whispering, in her treated ear.

Now 18 months old, Opal can respond to her parents’ voices and can communicate words such as “Dada” and “bye-bye.”

Opal’s mother, Jo Sandy, said: “When Opal could first hear us clapping unaided it was mind-blowing – we were so happy when the clinical team confirmed at 24 weeks that her hearing was also picking up softer sounds and speech. The phrase ‘near normal’ hearing was used and everyone was so excited such amazing results had been achieved.”

Auditory neuropathy can be due to a variation in a single gene, known as the OTOF gene. The gene produces a protein called otoferlin, needed to allow the inner hair cells in the ear to communicate with the hearing nerve. Approximately 20,000 people across the UK, Germany, France, Spain, Italy and UK and are deaf due to a mutation in the OTOF gene.

The CHORD trial, which started in May 2023, aims to show whether gene therapy can provide hearing for children born with auditory neuropathy. The trial in Cambridge is being supported by the NIHR Cambridge Clinical Research Facility and the NIHR Cambridge Biomedical Research Centre.

Professor Manohar Bance

Professor Manohar Bance, NIHR Cambridge BRC researcher and ear surgeon at Cambridge University Hospitals NHS Foundation Trust who is chief investigator of the trial, pictured left, said: “These results are spectacular and better than I expected. Gene therapy has been the future of otology and audiology for many years and I’m so excited that it is now finally here. This is hopefully the start of a new era for gene therapies for the inner ear and many types of hearing loss.”

Children with a variation in the OTOF gene often pass the newborn screening, as the hair cells are working, but they are not talking to the nerve. It means this hearing loss is not commonly detected until children are 2 or 3 years of age – when a delay in speech is likely to be noticed.

Professor Bance added: “We have a short time frame to intervene because of the rapid pace of brain development at this age. Delays in the diagnosis can also cause confusion for families as the many reasons for delayed speech and late intervention can impact a children’s development.”

“More than sixty years after the cochlear implant was first invented – the standard of care treatment for patients with OTOF related hearing loss – this trial shows gene therapy could provide a future alternative. It marks a new era in the treatment for deafness. It also supports the development of other gene therapies that may prove to make a difference in other genetic related hearing conditions, many of which are more common than auditory neuropathy.”

Mutations in the OTOF gene can be identified by standard NHS genetic testing. Opal was identified as being at risk as her older sister has the condition; this was confirmed by genetic test result when she was 3 weeks old.

Opal was given an infusion containing a harmless virus (AAV1). It delivers a working copy of the OTOF gene and is delivered via an injection in the cochlea during surgery under general anaesthesia. During surgery, while Opal was given the gene therapy in right ear, a cochlear implant was fitted in her left ear.

James Sandy, Opal’s father said: “It was our ultimate goal for Opal to hear all the speech sounds. It’s already making a difference to our day-to-day lives, like at bath-time or swimming, when Opal can’t wear her cochlear implant. We feel so proud to have contributed to such pivotal findings, which will hopefully help other children like Opal and their families in the future.”

Opal’s 24-week results, alongside other scientific data from the CHORD trial are being presented at the American Society of Gene and Cell Therapy (ASGC) in Baltimore, USA this week.

Dr Richard Brown, Consultant Paediatrician at CUH, who is an Investigator on the CHORD trial, said:  “The development of genomic medicine and alternative treatments is vital for patients worldwide, and increasingly offers hope to children with previously incurable disorders. It is likely that in the long run such treatments require less follow up so may prove to be an attractive option, including within the developing world. Follow up appointments have shown effective results so far with no adverse reactions and it is exciting to see the results to date.  

Within the new planned Cambridge Children’s Hospital, we look forward to having a genomic centre of excellence which will support patients from across the region to access the testing they need, and the best treatment, at the right time.”

Martin McLean, Senior Policy Advisor at the National Deaf Children’s Society, said: “Many families will welcome these developments, and we look forward to learning about the long-term outcomes for the children treated. This trial will teach us more about the effectiveness of gene therapy in those cases where deafness has a specific genetic cause.

“We would like to emphasise that, with the right support from the start, deafness should never be a barrier to happiness or fulfilment. As a charity, we support families to make informed choices about medical technologies, so that they can give their deaf child the best possible start in life.”

The CHORD trial is sponsored by Regeneron. Patients are being enrolled in the study in the US, UK and Spain.

Patients in the first phase of the study receive a low dose to one ear. The second phase are expected to use a higher dose of gene therapy in one ear only, following proven safety of the starting dose. The third phase will look at gene therapy in both ears with the dose selected after ensuring the safety and effectiveness in parts 1 and 2. Follow up appointments will continue for five years for enrolled patients, which will show how patients adapt to understand speech in the longer term.

World-first trial to provide hearing for children with rare type of genetic hearing loss launches in Cambridge

Addenbrooke’s Hospital in Cambridge is participating in a world-first trial to see whether gene therapy can provide hearing for children with severe to profound hearing loss due to a rare genetic condition.

The trial supported by the NIHR Cambridge BRC and NIHR Cambridge Clinical Research Facility, aims to show whether gene therapy can provide hearing for children born with hearing loss due to auditory neuropathy, a condition caused by the disruption of nerve impulses travelling from the inner ear to the brain.

Up to 18 children under the age of 18 years from three participating countries – the UK, Spain and the USA – will be included in the trial and followed up for five years to see the extent to which their hearing improves.

Auditory neuropathy can be due to a variation in a single gene – known as the OTOF gene – which produces a protein called otoferlin.  This protein typically allows the inner hair cells in the ear to communicate with the hearing nerve.  Mutations in the OTOF gene can be identified by standard NHS genetic testing. 

About 20,000 people across the US and EU5 (UK, Germany, France, Spain and Italy) are thought to have auditory neuropathy due to OTOF mutations.  Children with profound hearing loss face barriers developing communication skills and may miss developmental milestones if the right support is not provided from the start.

Professor Manohar Bance

Professor Manohar Bance, pictured left, an ear surgeon at Cambridge University Hospitals NHS Foundation Trust, and the chief investigator for the trial said: “Children with a variation in the OTOF gene are born with severe to profound hearing loss, but they often pass the new-born hearing screening so everyone thinks they can hear.  The hair cells are working, but they are not talking to the nerve.

“Gene therapy for otoferlin deficiency is the right starting point for young children because it’s among – if not the most – simple approaches for treating hearing loss; everything else should be intact and working normally.  Although experimental, the therapy could also potentially result in better quality hearing compared to cochlear implants.  But we have a short time frame to intervene because the young brain is developing so fast.” 

Intervening later in life becomes less effective as children may never fully form the ability to process the sounds of speech.  If successful for OTOF related hearing loss, gene therapy treatments could be extended to include people with hearing loss due to other more common genetic conditions.  

“It’s really important that we get the first gene therapy treatment right because it will allow us to proceed to treating other genetic conditions,” added Professor Bance.

Gene therapy aims to deliver a working copy of the faulty OTOF gene using a modified, non-pathogenic virus.  It will be delivered via an injection into the cochlea during surgery under general anesthesia. The procedure is similar to cochlear implant surgery, the current standard of care for OTOF related hearing loss.

The trial will consist of three parts, which must be done in order, with children receiving:

  1. A starting dose of gene therapy (DB-OTO) in one ear only.
  2. A higher dose of gene therapy in one ear only, following proven safety of the starting dose.
  3. Gene therapy in both ears with the optimal dose selected after ensuring the safety and effectiveness of DB-OTO in parts 1 and 2.

If the gene therapy is not effective for a child 6 months after treatment, the family can choose to receive a cochlear implant in the treated ear(s).

Ralph Holme, Director of Research and Insight at RNID said:“At RNID we are committed to a future where effective treatments for hearing loss are available for those who need and want them. Gene therapies have the potential to offer long lasting and permanent treatments for hearing loss, rather than merely managing the symptoms as hearing aids do. We welcome this pioneering trial, which we hope will lead to a treatment for children with OTOF related hearing loss and pave the way towards treatments for other genetic conditions.”

Martin McLean, Senior Policy Advisor at the National Deaf Children’s Society, said: “This is a significant development that will be of great interest to families of deaf children whose deafness is caused by a variation in the OTOF gene. The trial will help us to understand more about the effectiveness of gene therapy in improving hearing where deafness has a specific genetic cause.

“While some families will welcome being able to access this trial, it should be emphasised that with the right support from the start, deafness is not a barrier to achievement or happiness. Our role is to support families to make informed choices on whether they want to take up new treatments like this one which have the potential to mitigate the challenges their child might face.”

The trial is sponsored by Decibel Therapeutics, a Boston, US-based company specialising in gene therapies for hearing and balance disorders. DB-OTO is being developed by Decibel Therapeutics in collaboration with Regeneron Pharmaceuticals, Inc. It is supported by the National Institute for Health and Care Research (NIHR) Cambridge Clinical Research Facility and NIHR Cambridge Biomedical Research Centre.

Professor Bance also runs a multidisciplinary genetic hearing loss clinic to help improve the treatment and care of children with hearing disorders. These are examples of services that could be offered at the new Cambridge Children’s Hospital currently in planning.

All clinical trials that take place at Cambridge University Hospitals NHS Foundation Trust (CUHFT) are independently assessed for safety and quality by the Health Research Authority and Research Ethics Committee and complete the required legal and regulatory approvals before CUHFT agrees to participate. A team at the hospital has reviewed the safety protocols and all the necessary information; the trial will be performed and monitored by an experienced team of doctors, nurses and clinical support staff. All participating families give informed consent before treatment.

For more information about the CHORD clinical trial (NCT0578836), including eligibility criteria, please visit: Study Record | ClinicalTrials.gov

Researchers awarded prestigious Academy of Medical Sciences Fellowships

Four NIHR Cambridge BRC researchers have been elected to the Academy of Medical Sciences Fellowship.

Theme Leads Professors James Rowe and Serena Nik-Zainal, together with researchers Professors Charlotte Coles and Emanuele Di Angelantonio, received the awards in recognition of their outstanding biomedical and health research which has translated into benefits for patients and wider society.

James B. Rowe, Prof - Dementia
Neurodegenerative Disease and Dementias Theme Lead Professor James Rowe
Professor Serena Nik Zainal
Genomic Medicine Theme Lead Professor Serena Nik Zainal
Prof Charlotte Coles
Professor Charlotte Coles
Prof Emanuele Di Angelantonio
Prof Emanuele Di Angelantonio

Academy of Medical Sciences President Professor Dame Anne Johnson said: “These new Fellows are pioneering biomedical research and driving life-saving improvements in healthcare. It’s a pleasure to recognise and celebrate their exceptional talent by welcoming them to the Fellowship.”

  • This year Fellows were chosen from 353 candidates, and a shortlist of 126 candidates for peer review. To find out more about the Fellowship visit the Academy of Medical Sciences website.

Large number of stem cell lines carry significant DNA damage, say researchers

Cambridge researchers say detailed genetic characterisation including whole genome sequencing can help ensure safety of cell-based therapies

DNA damage caused by factors such as ultraviolet radiation affect nearly three-quarters of all stem cell lines derived from human skin cells, say Cambridge researchers, who argue that whole genome sequencing is essential for confirming if cell lines are usable.

Stem cells are a special type of cell that can be programmed to become almost any type of cell within the body. They are currently used for studies on the development of organs and even the early stages of the embryo.

Increasingly, researchers are turning to stem cells as ways of developing new treatments, known as cell-based therapies. Other potential applications include programming stem cells to grow into nerve cells to replace those lost to neurodegeneration in diseases such as Parkinson’s.

Originally, stem cells were derived from embryos, but it is now possible to derive stem cells from adult skin cells. These so-called induced pluripotent stem cells (iPSCs) have now been generated from a range of tissues, including blood, which is increasing in popularity due to its ease of derivation.

However, researchers at the University of Cambridge and Wellcome Sanger Institute have discovered a problem with stem cell lines derived from both skin cells and blood. When they examined the genomes of the stem cell lines in detail, they found that nearly three quarters carried substantial damage to their DNA that could compromise their use both in research and, crucially, in cell-based therapies. Their findings represent the largest genetic study to date of iPSCs and are published today in Nature Genetics.

DNA is made up of three billions pairs of nucleotides, molecules represented by the letters A, C, G and T. Over time, damage to our DNA, for example from ultraviolet radiation, can lead to mutations – a letter C might change to a letter T, for example. ‘Fingerprints’ left on our DNA can reveal what is responsible for this damage. As these mutations accumulate, they can have a profound effect on the function of cells and in some cases lead to tumours.

Dr Foad Rouhani from the Department of Surgery at the University of Cambridge and the Wellcome Sanger Institute said: “We noticed that some of the iPS cells that we were generating looked really different from each other, even when they were derived from the same patient and derived in the same experiment. The most striking thing was that pairs of iPS cells would have a vastly different genetic landscape – one line would have minimal damage and the other would have a level of mutations more commonly seen in tumours. One possible reason for this could be that a cell on the surface of the skin is likely to have greater exposure to sunlight than a cell below the surface and therefore eventually may lead to iPS cells with greater levels of genomic damage.”

The researchers used a common technique known as whole genome sequencing to inspect the entire DNA of stem cell lines in different cohorts, including the HipSci cohort at the Wellcome Sanger Institute and discovered that as many as 72% of the lines showed signs of major UV damage.

Professor Serena Nik Zainal

Professor Serena Nik-Zainal from the Department of Medical Genetics at the University of Cambridge, pictured right, said: “Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations – sometimes more than we find in tumours.  We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people.”

They decided to turn their attention to cell lines not derived from skin and focused on blood derived iPSCs as these are becoming increasingly popular due to the ease of obtaining blood samples. They found that while these blood-derived iPSCs, too, carried mutations, they had lower levels of mutations than skin-derived iPS cells and no UV damage. However, around a quarter carried mutations in a gene called BCOR, an important gene in blood cancers.

To investigate whether these BCOR mutations had any functional impact, they differentiated the iPSCs and turned them into neurons, tracking their progress along the way.

Dr Rouhani said: “What we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations – they had a tendency to favour other cell types instead. This is a significant finding, particularly if one is intending to use those lines for neurological research.”

When they examined the blood samples, they discovered that the BCOR mutations were not present within the patient: instead, the process of culturing cells appears to increase the frequency of these mutations, which may have implications for other researchers working with cells in culture.

Scientists typically screen their cell lines for problems at the chromosomal level – for example by checking to see that the requisite 23 pairs of chromosomes are present. However, this would not be sufficiently detailed to pick up the potentially major problems that this new study has identified. Importantly, without looking in detail at the genomes of these stem cells, researchers and clinicians would be unaware of the underlying damage that is present with the cell lines they are working with.

“The DNA damage that we saw was at a nucleotide level,” says Professor Nik-Zainal. “If you think of the human genome as like a book, most researchers would check the number of chapters and be satisfied that there were none missing. But what we saw was that even with the correct number of chapters in place, lots of the words were garbled.”

Fortunately, says Professor Nik-Zainal, there is a way round the problem: using whole genome sequencing to look in detail for the errors at the outset.

“The cost of whole genome sequencing has dropped dramatically in recent years to around £500 per sample, though it’s the analysis and interpretation that’s the hardest bit. If a research question involves cell lines and cellular models, and particularly if we’re going to introduce these lines back into patients, we may have to consider sequencing the genomes of these lines to understand what we are dealing with and get a sense of whether they are suitable for use.”

Dr Rouhani adds: “In recent years we have been finding out more and more about how even our healthy cells carry many mutations and therefore it is not a realistic aim to produce stem cell lines with zero mutations. The goal should be to know as much as possible about the nature and extent of the DNA damage to make informed choices about the ultimate use of these stem cell lines.

“If a line is to be used for cell based therapies in patients for example, then we need to understand more about the implications of these mutations so that both clinicians and patients are better informed of the risks involved in the treatment.”

The research was funded by Cancer Research UK, the Medical Research Council and Wellcome, and supported by NIHR Cambridge Biomedical Research Centre and the UK Regenerative Medicine Platform.

Paper Reference

Rouhani, FJ, Zou, X, Danecek, P, et al. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells; Nat Gen; 11 Aug 2022; DOI: 10.1038/s41588-022-01147-3

Cambridge researchers to receive nearly £4m to tackle cancer roadblocks

NIHR Cambridge BRC researchers are among the Cambridge scientists to receive £3,938,500 as part of Cancer Grand Challenges, a major initiative co-founded by Cancer Research UK and the National Cancer Institute in the US, which aims to encourage the world’s leading cancer researchers to take on some of the toughest challenges in cancer research.

The eDyNAmiC (extrachromosomal DNA in Cancer) team will investigate new ways to combat treatment resistant cancers, while the CANCAN (CANcer Cachexia Action Network) team hopes to prevent cachexia, where patients ‘waste away’ in the later stages of their disease.

Funding for the Cambridge-based projects is part of an overall £80 million awarded this week to four elite global teams who will deepen our understanding of cancer through international collaboration leading to new advances for people with cancer.

Extrachromosomal DNA – present in up to a third of all tumours, helps to evade treatment

The Stanford University-led eDyNAmiC team, which includes Professor Serena Nik Zainal at the University of Cambridge, hopes to tackle tumour evolution, which is driven by circular pieces of tumour DNA which exist outside the tumour and pose a major problem by enabling tumours to resist treatment.

Research is now revealing that a major driver of tumour evolution is extrachromosomal DNA (ecDNA). These small circular DNA particles enable cells to rapidly change their genomes and so evade the immune system.

EcDNA doesn’t follow the rules of normal chromosomes, providing tumours a way to evolve and change their genomes to evade treatment.  

Although first observed in cancer in 1965, researchers are only beginning to understand the extent to which it is prevalent in around a third of cancers and how it helps tumours to become more resistant, aggressive and affect patient survival.

The goal of eDyNAmiC is to understand how extrachromosomal DNA is created, to find vulnerabilities and then to develop new ways to target these in some of the hardest cancers to treat, including glioblastoma, lung and oesophageal cancer.

Co-investigator Professor Nik-Zainal (pictured, below), of the University of Cambridge Early Cancer Institute and Department of Medical Genetics, said: “My team and I are so excited to be part of this collaboration studying this phenomenon of extra pieces of DNA called ecDNA.

Professor Serena Nik Zainal
Professor Serena Nik-Zainal. Photo: Chris Radburn

“What a privilege it is to be entrusted to explore how ecDNAs cause cancer and drive them to be aggressive. We hope that what we learn will bring real benefits to cancer patients in due course.”

Research aims to improve quality of life for patients with cancer cachexia

The CANCAN team is led by US researchers who will work with co-investigators Professor Sir Stephen O’Rahilly and Dr Tony Coll, of the Wellcome-MRC Institute of Metabolic Science, and Dr Giulia Biffi, of the CRUK Cambridge Institute, to explore the underpinning mechanisms behind cancer cachexia – a debilitating wasting condition many people experience in the later stages of the disease.

L-r: Dr Giulia Biffi, Professor Sir Stephen O’Rahilly and Dr Tony Coll at Cancer Research UK in Cambridge. Photo: Chris Radburn

Cachexia syndrome is characterised by poor appetite and extensive weight loss from both skeletal muscle and fatty tissue and is still not fully understood.

It is hoped further research can help develop new treatments to improve quality of life for cancer patients and set the standard for cachexia management around the world.

Professor Sir Stephen O’Rahilly said: “For many decades we have studied how a range of hormones act on the brain to regulate appetite and body weight.

“Many of the insights that we have gained through our previous research in obesity are likely to be highly relevant to cancer cachexia, a condition where hormonal and metabolic changes secondary to cancer impact on the brain to reduce, rather than increase appetite.

“We have recently discovered a pathway in the brain which is key to controlling whether we put food calories in excess of our basic needs into fat or into muscle.  This pathway is likely to be highly relevant to patients with cancer cachexia who are particularly affected by a loss of muscle.”  

Dr Giulia Biffi’s research focuses on understanding the biology of the tumour microenvironment in pancreatic cancer with the aim of developing new treatments and diagnostics.

Dr Biffi, who co-leads the CRUK Cambridge Centre Pancreatic Cancer Programme, said: “Cachexia is predominant in pancreatic cancer patients; it increases patient mortality and can prevent patients accessing treatment as they are too weak. If we can identify ways to treat cachexia more people could be treated for their cancer.

“This is a fantastic opportunity to interact with a highly multi-disciplinary team to bring our different scientific and clinical strategies towards a single common goal.”

  • Dr Coll with Dr Claire Connell have recently opened a clinical study at Addenbrooke’s hospital which aims to understand the mechanisms underlying weight loss in cancer patients by investigating changes to metabolism and the immune system. They hope the findings from the Metabolic and Immunological Phenotyping in Patients with Cancer (MIPPaC) study will guide future research and help to design treatments that can alleviate or prevent weight loss and improve outcomes for cancer patients.

New genomic testing provides vital diagnosis for severely ill babies

More than a third of severely sick babies referred for rapid whole genome sequencing receive vital genetic diagnosis in latest study across the East of England.

Results from the latest Cambridge genomic study supported by NIHR Cambridge BRC and NIHR BioResource, confirm rapid whole genome sequencing (WGS) as an effective early test to aid diagnosis in severely ill children.

WGS can determine variations in any part of the genome. By looking at all the genes in the genome it is possible to uncover disease-causing changes with a single test. This is important as some of the findings can be in unexpected genes.

Building on the findings from the Next Generations Children’s Project (2019), over 500 seriously ill children and their parents across the East of England – average age of 8.5 months – were recruited from several paediatric service settings. The aim was to provide greater insight into the benefits of rapid WGS compared to other routine genetic tests in areas such as neonatal intensive care units (NICU), paediatric intensive care units (PICU), paediatric neurology clinics and clinical genetics clinics.

Researchers worked hand in hand with scientists at East Genomic Laboratory Hub, based in Addenbrooke’s hospital, Cambridge to deliver the testing.

Findings illustrate that children in all four settings benefited from WGS testing at an early stage of their diagnoses, with patients referred from neurology having the highest percentage of confirmed diagnosis (46%), 31 % in PICU and 25% in NICU. Diagnostic rates were highest in patients with neurodevelopmental delay, hypotonia, seizures or suspected mitochondrial disorder.

In 90% of cases, both parents contributed DNA samples alongside their child in tests known as a ‘trio analysis’, which is now the gold standard test within the NHS. Comparing patient’s and parents’ DNA changes allows for identification of new information on known disease-causing genes and for the discovery of several new genes not suspected prior to testing.

Professor Lucy Raymond - Integrative Genomics theme lead

Professor Lucy Raymond, Professor of Medical Genetics and Neurodevelopment at the University of Cambridge and Honorary Consultant at Cambridge University Hospitals NHS Foundation Trust, pictured right, commented: “We found that overall one in three patients received a vital diagnosis and importantly more than one in five diagnoses would have been missed without the broad analysis carried out by WGS testing. Diagnoses that were identified included spinal muscular atrophy (SMA) and other neurodegenerative conditions including some rare epilepsies, which are now eligible for precision medical therapies in the NHS.

“Finding a diagnosis changes management, stops unnecessary tests, and reassures families that everything has been done that can be done for their child.

“Rapid parent and child WGS (or trio) analysis is an excellent single test suitable for many patients as soon as possible on admission to hospital or specialist clinic. However, this must be supported by sufficient training for clinicians as well as scientific expertise for robust analysis of results.”

Many genes that can cause a rare disease have not yet been identified, so a negative result – or an unconfirmed diagnosis – does not mean a condition isn’t genetic. It does however highlight the need to keep looking at the genome to find new genes that cause disease and to help clinicians and families in the future.

Professor Raymond added: “Continuing follow-up of families within national genomic research databases such as the NIHR Bioresource or the National Genomics Research Library enables involvement in further social and health research and new genomic discoveries alongside potential recruitment to clinical trials beneficial to patients.”

Professor David Rowitch - Paediatrics theme lead

Professor David Rowitch, Paediatrician (neonatology) and developmental neuroscientist and NIHR Cambridge BRC paediatric theme lead, pictured left, said: “The study highlights that the burden of genetic disorders in paediatric inpatient and specialist clinic settings is much higher than previously suspected. The finding that children in neurology have a 46% rate of diagnosis by WGS is likely to be quite surprising to many clinicians.”

“It also shows that frequent re-analysis of patient WGS data improved the diagnostic rate as new genes were confirmed and published by other sources. Moreover, by sharing data and contributing to the international rare disease endeavours, other patients can hopefully receive a potential diagnosis.”

Dr Topun Austin, Consultant Neonatologist, Neonatal Intensive Care Unit CUH commented: “The time taken to reach a diagnosis in these children can often be prolonged, requiring multiple tests and consultations. Rapid trio WGS in the NICU has enabled newborn infants with complex illness to be diagnosed at an earlier stage, which can significantly impact on their management.

“This study supports the 2019 research findings and provides further evidence of the value of rapid WGS to staff and patients. The NHS now provides rapid sequencing across all NICU and PICUs in the UK clearly showing how research can make a meaningful impact on clinical care”.

Jo Balfour, Managing Director, Cambridge Rare Disease Network commented: “It is the most worrying time for a family when their child is unwell and the reason is unknown. Whilst rapid WGS does not promise a clear diagnosis for every child with a rare health condition, research that supports advances in genomic testing to help more children and their families is welcome”.

The research was supported by the NIHR Cambridge Biomedical Research Centre, NIHR Rare Disease Bioresource, The Rosetrees Trust, and Isaac Newton Trust. Thanks also to Health Education England’s Higher Specialist Scientist Training programme which enabled East GLH staff time on this project. 

Children with cancer benefit from whole genome sequencing

More than 100 children with cancer from across the East of England have had their tumours tested by whole genome sequencing at Addenbrookes Hospital and supported by the NIHR Cambridge BRC, to help improve their diagnosis and treatment.

In cancer, Whole Genome Sequencing looks at the ‘whole genome’ or entire genomic (DNA) profile of a patient as well as the cancer.

For children with cancer, scientists look for differences, known as ‘variants’ or ‘mutations’, in the DNA from their tumour compared with their blood. This helps doctors and scientists give a far more detailed and personalised diagnosis, in some cases providing clues to the most effective treatments for each patient. Data from the first 36 children, who consented to the test as part of the national 100,000 Genome Project cohort, has now been published in the British Journal of Cancer.

The published findings, also shared at the 2021 National Cancer Research Institute (NCRI) Festival, described 23 different solid tumour types, and revealed several potentially important variants. In a number of cases, the information either refined or changed the children’s diagnosis, revealed new information about the children’s prognoses, showed hereditary causes, or revealed treatments that might not otherwise have been considered.

A further 65 patients across the region have had their whole genomes read since the test was made routinely available through the NHS Genomic Medicine Service at the start of 2021. Early review of the data and outcomes shows that these results continue to demonstrate the value of centralised WGS for children with cancer.

Aubrey, from Bedfordshire, was diagnosed with cancer in January 2021 when she was only 16 months old. However, as the actual type of Aubrey’s cancer was not certain from standard testing, her parents Anna and Paul agreed to a WGS test for Aubrey.

Aubrey with her dad and Professor Matt Murray

Anna, Aubrey’s mother said: “The test gave us a confirmed diagnosis for Aubrey after other tests had narrowed it down to one of two potential types of cancer. The result meant that the clinicians could be more confident as to the best treatment to use.

“Whist we still have a challenging journey with Aubrey’s diagnosis and treatment, we were relieved to know that she did not have cancer that was inherited, and hence we did not have to worry that it could affect our son or other members of the family as well.

Professor Matthew Murray

Professor Matthew Murray, Honorary Consultant Paediatric Oncologist, Cambridge University Hospitals, pictured left, said: “Seeing 100 children with cancer benefit from WGS is a milestone. Overall, as a result of these tests, we’ve been able to confirm or refine the diagnosis for many of the children, identify and in some cases start new and beneficial treatment, and importantly in others have a clearer idea of the likely course of a patient’s cancer.”

Following referral, the NHS pathway allows patients and family to meet the clinical team at CUH to discuss the next steps.

Once consent to WGS had been obtained, a sample of tumour (usually taken from a previous procedure) is sent alongside a blood sample via the NHS East Genomic Laboratory Hub (NHS East GLH) to the company Illumina – located a few miles away from CUH. Samples are then sequenced at Illumina and results sent back for discussion at a meeting with the patient’s clinical team as well as expert scientists from the NHS East GLH to decide on best patient management.

This data has been released to coincide with the publication of the results from the patients enrolled in the 100,000 genome project in the British Journal of Cancer.

The research was supported by the NIHR Cambridge Biomedical Research Centre.

Adapted from CUH press release

Largest study of whole genome sequencing data reveals new clues to causes of cancer

DNA analysis of thousands of tumours from NHS patients has found a ‘treasure trove’ of clues about the causes of cancer, with genetic mutations providing a personal history of the damage and repair processes each patient has been through.

In the biggest study of its kind, a team of scientists led by Professor Serena Nik-Zainal from Cambridge University Hospitals (CUH) and University of Cambridge and supported by the NIHR Cambridge BRC, analysed the complete genetic make-up or whole-genome sequences (WGS) of more than 12,000 NHS cancer patients.   

Because of the vast amount of data provided by whole genome sequencing, the researchers were able to detect patterns in the DNA of cancer, known as ‘mutational signatures’, that provide clues about whether a patient has had a past exposure to environmental causes of cancer such as smoking or UV light, or has internal, cellular malfunctions.

The team were also able to spot 58 new mutational signatures, suggesting that there are additional causes of cancer that we don’t yet fully understand.

This research was supported by Cancer Research UK and published on Friday 22nd April 2022 in the journal ‘Science’ here: http://www.science.org/doi/10.1126/science.abl9283

The genomic data were provided by the 100,000 Genomes Project  an England-wide clinical research initiative to sequence 100,000 whole genomes from around 85,000 patients affected by rare disease or cancer.

Dr Andrea Degasperi, research associate at the University of Cambridge and first author said:

“WGS gives us a total picture of all the mutations that have contributed to each person’s cancer.  With thousands of mutations per cancer, we have unprecedented power to look for commonalities and differences across NHS patients, and in doing so we uncovered 58 new mutational signatures and broadened our knowledge of cancer.”

Serena Nik-Zainal, a professor of genomic medicine and bioinformatics at the University of Cambridge, NIHR Cambridge BRC researcher and honorary consultant in clinical genetics at CUH said:

“The reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene – they help to pinpoint cancer culprits. Some mutational signatures have clinical or treatment implications – they can highlight abnormalities that may be targeted with specific drugs or may indicate a potential ‘Achilles heel’ in individual cancers.”

“We were able to perform a forensic analysis of over 12,000 NHS cancer genomes thanks to the generous contribution of samples from patients and clinicians throughout England.  We have also created FitMS, a computer-based tool to help scientists and clinicians identify old and new mutational signatures in cancer patients, to potentially inform cancer management more effectively.”

Michelle Mitchell, chief executive of Cancer Research UK, said: “This study shows how powerful whole genome sequencing tests can be in giving clues into how the cancer may have developed, how it will behave and what treatment options would work best.  It is fantastic that insight gained through the NHS 100,000 Genomes Project can potentially be used within the NHS to improve the treatment and care for people with cancer.”

Professor Matt Brown, chief scientific officer of Genomics England said: “Mutational signatures are an example of using the full potential of WGS.  We hope to use the mutational clues seen in this study and apply them back into our patient population, with the ultimate aim of improving diagnosis and management of cancer patients.”

Professor Dame Sue Hill, chief scientific officer for England and Senior Responsible Officer for Genomics in the NHS said: “The NHS contribution to the 100,000 Genomes Project was vital to this research and highlights how data can transform the care we deliver to patients, which is a cornerstone of the NHS Genomic Medicine Service.”

Adapted from CUH press release

Award given to build data ‘bridge’ that could revolutionise precision medicine

NIHR Cambridge Biomedical Research Centre (NIHR Cambridge BRC), together with Genomics England (GEL), Eastern Academic Health Science Network (Eastern AHSN) and the precision medicine software company Lifebit have been awarded £200,000 by UK Research and Innovation as part of the DARE UK (Data and Analytics Research Environments UK) programme, to develop and test a ‘bridge’ between health data at the NIHR Cambridge BRC and GEL’s clinical genetic data – which will allow researchers to work with their combined data, without any data leaving either source.

“The more health data available for research, the more powerful it is – and through the NHS and research organisations such as NIHR and GEL, the UK has a lot of biomedical research data that could hold the key to understanding, diagnosing, and treating health conditions. 

Prof. Serena Nik-Zainal

“However, data are often locked up in different locations due to the size of the data and to maintain privacy and security, ultimately preventing researchers from using it to its full potential,” explains Professor Serena Nik-Zainal, consortium lead and Genomic Medicine theme lead at NIHR Cambridge BRC, pictured right.

Organisations often store their data in spaces known as ‘Trusted Research Environments’ (TREs) – secure spaces for researchers to access and analyse sensitive data to help prevent unauthorised access and re-identification of individuals from anonymised data.

The DARE UK award will bring together a consortium to create and test a ‘bridge’ that will enable their respective TRE’s to ‘talk’ to one another (known as ‘federation’). Importantly, this bridging technology will be open source, meaning the global research community will be able to benefit from the collaborative potential of this technology.

Lifebit is already successfully working with GEL, having launched in 2020 a next-generation genomic medicine research platform that has been central to the UK Government’s research response to COVID-19, as well as facilitating medical advancements in cancer and rare diseases. This will be key to bridging the two datasets of Genomics England and the NIHR Cambridge BRC, in what will be the first federated architecture between a national project and a higher education institution.

As well as designing and testing the ‘bridging’ Federation infrastructure, the project aims to develop new standards to inform how federated TREs communicate securely and power largescale research analyses going forward. 

All health data ultimately comes from patients themselves, and patient and public involvement has been essential from the outset.  Consortium patient partner Rosanna Fennessy explains: “Patients also need answers about their conditions that hopefully patient data can provide.  It is important to bring together all forms of expertise – patients, clinicians, researchers and data experts to design ways to safely and securely maximise the use of data for research.”  The consortium will work with Rosanna, and patient groups across the UK to develop data governance and ethics frameworks, and federation best practices.

Professor Serena Nik-Zainal concludes: “We want to use health data to fix real, human problems and to narrow the gap between clinicians and computational experts working on health data for research. 

“This starts with building the infrastructure, the machinery we need to be able to take advantage of the amazing data resources that we have to realise the potential of the data to improve patient lives.”    

Find out more in this short video with Professor Serena Nik-Zainal.

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