̽��ֱ�� of Cambridge - Genomics England

Collaboration Award 2023

zs332 — Wed, 13 Dec 2023 08:32:38 +0000

̽��ֱ��2023 Collaboration Awards goes to UK Citizens' Jury on Human Embryo Editing, led by Professor Anna Middleton, Director Kavli Centre for Ethics, Science, and the Public.

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

sc604 — Thu, 21 Apr 2022 18:00:00 +0000

In the biggest study of its kind, a team of scientists led by Professor Serena Nik-Zainal from Cambridge ̽��ֱ�� Hospitals (CUH) and the ̽��ֱ�� of Cambridge, 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.

̽��ֱ��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. ̽��ֱ��results are reported in the journal Science.

̽��ֱ��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.

“WGS gives us a total picture of all the mutations that have contributed to each person’s cancer,” said first author Dr Andrea Degasperi, from Cambridge’s Department of Oncology. “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.”

“ ̽��ֱ��reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene - they help to pinpoint cancer culprits,” said Serena Nik-Zainal, from the Department of Medical Genetics and an honorary consultant in clinical genetics at CUH. “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, which funded the research, 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:

“ ̽��ֱ��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.”

Reference:
Andrea Degasperi et al. ‘Substitution mutational signatures in whole-genome–sequenced cancers in the UK population.’ Science (2022). DOI: 10.1126/science.abl9283

Adapted from a CUH press release.

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.

̽��ֱ��reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene - they help to pinpoint cancer culprits

Serena Nik-Zainal

Largest dataset of cancer whole genome sequences | Serena Nik-Zainal

Isaac Brownell, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH

Merkel Cell Carcinoma

̽��ֱ��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.

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Cambridge spin-out aims to realise the power of genomic data in precision medicine

skbf2 — Wed, 02 Feb 2022 12:00:58 +0000

XetaBase is built on the open-source OpenCB platform, the first proven big data system optimised for genomic data. ̽��ֱ��result of a five-year collaboration between Genomics England and the ̽��ֱ�� of Cambridge, OpenCB enables genotypes to be stored in a database.

̽��ֱ��lead developer of OpenCB, Ignacio Medina, is Head of the Computational Biology Lab at the ̽��ֱ�� of Cambridge and Zetta Genomics’ founder and co-developer of XetaBase.

XetaBase allows researchers and clinicians to securely store, easily access, and dynamically interrogate vast and increasing volumes of genomic data – on demand. ̽��ֱ��technology brings genome-enabled discovery, healthcare analytics, and population research into the lab – and prognostics, diagnostics, and therapeutics into the clinic.

Zetta Genomics founder, Ignacio Medina said, “Zetta Genomics re-imagines data to deliver a dynamic platform fit for the fast-emerging, fast-scaling, multi-petabyte environment. In liberating genomic data – placing its power into the hands of researchers and clinicians – we will drive precision medicine’s transformation into mainstream healthcare and life-changing patient benefit.”

̽��ֱ��seed funding round comes as genome-enabled precision medicine moves from the niche to the mainstream. ̽��ֱ��UK has led the world with its new Genomics Medicine Service, making testing routine within the publicly funded NHS. These and other population level initiatives are predicted to see 60 million genomes sequenced to 2025 and 100 million by the end of the decade.

Marc Subirats, Partner at lead investor, Nina Capital, said, “Genomic medicine has enjoyed explosive growth in the past five years, but this is set to be eclipsed in the next decade. XetaBase is an enabling technology – empowering virtually every research field and clinical application. As genomic sequencing moves from the hundreds of thousands to the hundreds of millions, Nina Capital is confident that Zetta Genomics’ growth will both drive and be driven by rapid advances in precision medicine.”

Market and precision medicine opportunities have helped Zetta Genomics to create an extensive, growing and valuable partnership network with organisations such as Fujitsu, Future Perfect Healthcare, Genomics England, Microsoft, the NHS, and the ̽��ֱ�� of Cambridge.

Dr Elaine Loukes, Investment Director at ̽��ֱ�� of Cambridge Enterprise, said, “Cambridge Enterprise creates and invests in companies, built on ̽��ֱ�� of Cambridge research, that can have a huge positive impact on society. From our first meeting it was clear that Ignacio had developed something incredibly special. Zetta’s technology helps researchers and clinicians fully exploit genomic data, speeding the delivery of precision medicine across the world.”

VC-backed funding will focus on growth, enhancing the company’s partnership network while it expands from the UK to open both Spanish and US offices. Investment will also focus on talent, with a five-fold increase in headcount to secure additional software, development and commercialisation expertise.

Cambridge spin-out Zetta Genomics has raised £2.5 million in new seed funding from Nina Capital, APEX Medical and Cambridge Enterprise to advance its genomic data management technology and power the discovery and delivery of precision medicine at scale.

Zetta Genomics

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Whole genome sequencing increases diagnosis of rare disorders by nearly a third

ta385 — Thu, 04 Nov 2021 06:00:00 +0000

Mitochondrial disorders affect around 1 in 4,300 people and cause progressive, incurable diseases. They are amongst the most common inherited diseases but are difficult for clinicians to diagnose, not least because they can affect many different organs and resemble many other conditions.

Current genetic testing regimes fail to diagnose around 40% of patients, with major implications for patients, their families and the health services they use.

A new study, published in the BMJ, offers hope to families with no diagnosis, and endorses plans for the UK to establish a national diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.

While previous studies based on small, highly selected cohorts have suggested that WGS can identify mitochondrial disorders, this is the first to examine its effectiveness in a national healthcare system – the NHS.

̽��ֱ��study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the ̽��ֱ�� of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project which was set up to embed genomic testing in the NHS, discover new disease genes and make genetic diagnosis available for more patients.

In total, 345 participants – aged 0 to 92 with a median age of 25 years – had their whole genome sequenced. Through different analyses, the researchers found that they could make a definite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more invasive, failed to reach these diagnoses. Six possible diagnoses (2% of the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were actually non-mitochondrial disorders, with some having specific treatments. This happened because so many different diseases resemble mitochondrial disorders, making it very difficult to know which are which.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said:

“We recommend that whole genome sequencing should be offered early and before invasive tests such as a muscle biopsy. All that patients would need to do is have a blood test, meaning that this could be offered across the whole country in an equitable way. People wouldn’t need to travel long distances to multiple appointments, and they would get their diagnosis much faster.”

Dr Katherine Schon from the MRC Mitochondrial Biology Unit and the Departments of Clinical Neuroscience and Medical Genetics, said:

“A definitive genetic diagnosis can really help patients and their families, giving them access to tailored information about prognosis and treatment, genetic counselling and reproductive options including preimplantation genetic diagnosis or prenatal diagnosis.”

̽��ֱ��researchers made 37.5% of their diagnoses in genes known to cause mitochondrial disease. These diagnoses were nearly all unique to a particular participant family, reflecting the genetic diversity found in these disorders. ̽��ֱ��impairment of mitochondrial function tends to affect tissues with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles. ̽��ֱ��study offers a valuable new resource for the discovery of future mitochondrial disease genes.

̽��ֱ��majority of the team’s diagnoses (62.5%) were, however, of non-mitochondrial disorders which had features resembling mitochondrial diseases. These disorders would have been missed if the participants had only been investigated for mitochondrial disorders through muscle biopsy and/or a specific mitochondrial gene panel. These participants were living with a range of conditions including developmental disorders with intellectual disability, severe epileptic conditions and metabolic disorders, as well as heart and neurological diseases.

Chinnery said: “These patients were referred because of a suspected mitochondrial disease and the conventional diagnostic tests are specifically for mitochondrial diseases. Unless you consider these other possibilities, you won't diagnose them. Whole genome sequencing isn’t restricted by that bias.”

A small number of newly diagnosed participants are already receiving treatments as a result. ̽��ֱ��team identified potentially treatable disorders in six participants with a mitochondrial disorder and nine with a non-mitochondrial disorder, but the impact of the treatments has yet to be determined.

Chinnery said: “Diagnostic services are fragmented and unevenly distributed across the UK, and that creates major challenges for people with rare diseases and their families. By delivering a national programme based on this genome-wide approach, you can offer the same level of service to everyone."

Schon said: “If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials so we can get definitive evidence that new treatments work.”

̽��ֱ��study points out that the relatively high number of patients with probable or possible diagnoses reflects the need for greater investment into the analysis of functional effects of new genetic variants which could be the cause of disease, but it is not certain at present.

It also argues that rapid trio whole genome sequencing should be offered to all acutely unwell individuals with suspected mitochondrial disorders, so that results can help guide clinical management. Currently in the UK, this is only available for acutely unwell children.

Dr Ellen Thomas, Clinical Director and Director of Quality at Genomics England, said:

“We are very pleased to see significant research like this being enabled by data generously donated by participants of the 100,000 Genomes Project. It is clear from these results how their contributions to a rich and, importantly, secure dataset is critical in facilitating the genomic research that leads to insights like these that then have the potential to return value to the NHS and their patients. We look forward to seeing how these findings could support future care for patients with suspected mitochondrial disorders.”

Reference

KR Schon et al., ‘Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study’, BMJ (2021). DOI: 10.1136/ bmj-2021-066288

Funding

National Institute for Health Research, NHS England, Wellcome, Cancer Research UK and the Medical Research Council within UK Research and Innovation

Whole genome sequencing from a single blood test picks up 31% more cases of rare genetic disorders than standard tests, shortening the ‘diagnostic odyssey’ that affected families experience, and providing huge opportunities for future research.

A definitive genetic diagnosis can really help patients and their families

Patrick Chinnery

Belova59 via Pixabay

Gloved hand holding two blood samples

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New cancer algorithm flags genetic weaknesses in tumours

Anonymous — Mon, 26 Apr 2021 23:01:00 +0000

The MMRDetect clinical algorithm makes it possible to identify tumours that have ‘mismatch repair deficiencies’ and then improve the personalisation of cancer therapies to exploit those weaknesses.

̽��ֱ��study, led by researchers from the ̽��ֱ�� of Cambridge’s Department of Medical Genetics and MRC Cancer Unit, identified nine DNA repair genes that are critical guardians of the human genome from damage caused by oxygen and water, as well as errors during cell division.

̽��ֱ��team used a genome editing technology, CRISPR-Cas9, to ‘knock out’ (make inoperative) these repair genes in healthy human stem cells. In doing so, they observed strong mutation patterns, or mutational signatures, which offer useful markers of those genes and the repair pathways they are involved in, failing.

̽��ֱ��study, funded by Cancer Research UK and published today in the journal Nature Cancer, suggests that these signatures of repair pathway defects are on-going and could therefore serve as crucial biomarkers in precision medicine.

Senior author, Dr Serena Nik-Zainal, a Cancer Research UK Advanced Clinician Scientist at Cambridge ̽��ֱ��’s MRC Cancer Unit, said: “When we knock out different DNA repair genes, we find a kind of fingerprint of that gene or pathway being erased. We can then use those fingerprints to figure out which repair pathways have stopped working in each person’s tumour, and what treatments should be used specifically to treat their cancer.”

̽��ֱ��new computer algorithm, MMRDetect, uses the mutational signatures that were identified in the knock out experiments, and was trained on whole genome sequencing data from NHS cancer patients in the 100,000 Genomes Project, to identify tumours with ‘mismatch repair deficiency’ which makes them sensitive to checkpoint inhibitors, immunotherapies. Having developed the algorithm on tumours in this study, the plan now is to roll it out across all cancers picked up by Genomics England.

̽��ֱ��breakthrough demonstrates the value of researchers working with the 100,000 Genomes Project, a pioneering national whole genome sequencing endeavour.

Parker Moss, Chief Commercial and Partnerships Officer at Genomics England, said: “We are very excited to see such impactful research being supported by the 100,000 Genomes Project, and that our data has helped to develop a clinically significant tool. This is a fantastic example of how the sheer size and richness of the 100,000 Genomes Project data can contribute to important research.

“ ̽��ֱ��outcomes from Dr Nik-Zainal and her team’s work demonstrate perfectly how quickly and effectively we can return value to patient care by bringing together a community of leading researchers through Genomics England’s platform.”

̽��ֱ��study offers important insights into where DNA damage comes from in our bodies. Water and oxygen are essential for life but are also the biggest sources of internal DNA damage in humans.

Dr Nik-Zainal said: “Because we are alive, we need oxygen and water, yet they cause a constant drip of DNA damage in our cells. Our DNA repair pathways are normally working to limit that damage, which is why, when we knocked out some of the crucial genes, we immediately saw lots of mutations.”

“Some DNA repair genes are like precision tools, able to fix very specific kinds of DNA damage. Human DNA has four building blocks: adenine, cytosine, guanine and thymine. As an example, the OGG1 gene has a very specific role of fixing guanine when it is damaged by oxygen. When we knocked out OGG1, this crucial defence was severely weakened resulting in a very specific pattern of guanines that had mutated into thymines throughout the genome.”

To be most effective, the MMRDetect algorithm could be used as soon as a patient has received a cancer diagnosis and their tumour characterised by genome sequencing. ̽��ֱ��team believes that this tool could help to transform the way a wide range of cancers are treated and save many lives.

Michelle Mitchell, Chief Executive of Cancer Research UK, said: “Determining the right treatments for patients will give them the best chance of surviving their disease. Immunotherapy in particular can be powerful, but it doesn’t work on everyone, so figuring out how to tell when it will work is vital to making it the most useful treatment it can be.

“Our ability to map and mine useful information from the genomes of tumours has improved massively over the past decade. Thanks to initiatives like the 100,000 Genomes Project, we are beginning to see how we might use this information to benefit patients. We look forward to seeing how this research develops, and its possibilities in helping future patients.”

This study was funded by Cancer Research UK (CRUK), Wellcome, Medical Research Council, Dr Josef Steiner Foundation and supported by the Cambridge NIHR Biomedical Research Campus.

Reference

Xueqing Zou et al., 'A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage', Nature Cancer (26 April 2021). DOI: 10.1038/s43018-021-00200-0.

A new way to identify tumours that could be sensitive to particular immunotherapies has been developed using data from thousands of NHS cancer patient samples sequenced through the 100,000 Genomes Project.

Dr Serena Nik-Zainal

Yes

Interplay between mitochondria and the nucleus may have implications for changing cell’s ‘batteries’

cjb250 — Thu, 23 May 2019 18:00:47 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, suggests that matching mitochondrial DNA to nuclear DNA could be important when selecting potential donors for the recently-approved mitochondrial donation treatment, in order to prevent potential health problems later in life.

Almost all of the DNA that makes up the human genome – the body’s ‘blueprint’ – is contained within our cells’ nuclei. This is referred to as ‘nuclear DNA’. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as the ‘batteries’ that provide the energy for our cells to function. Each of these mitochondria is coded for by a tiny amount of ‘mitochondrial DNA’. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

Until now, scientists had thought that mitochondria were readily interchangeable, serving only to power our bodies, and so an individual’s mitochondria could be replaced with those from a donor with no consequences. However, in the first major population study to use data from the UK-wide 100,000 Genomes Project and its National Institute for Health Research (NIHR)-funded pilot project, researchers compared mitochondrial and nuclear DNA from tens of thousands of people and found that mitochondria may be fine-tuned to the nucleus.

̽��ֱ��researchers studied over 1,500 mother-child pairs and found that just under a half (45%) of individuals within these pairs harboured mutations affecting at least 1% of their mitochondrial DNA. Mutations in certain parts of mitochondrial DNA were more likely to be transmitted, such as those in the so-called D-loop region, which controls how mitochondrial DNA copies itself. Conversely, mutations in other parts of mitochondrial DNA were more likely to be suppressed, such as the code for how mitochondria produce their own proteins.

“Children inherit their DNA exclusively from their mother and we wanted to see how this explains the origins of mitochondrial diseases,” says first author Dr Wei Wei from the Medical Research Council (MRC) Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge. “What we found was that there is some kind of selection taking place when mitochondrial DNA is transmitted down a generation, allowing some mutations to be passed on and others to be blocked.”

Genetic variants that had previously been observed around the world were more likely to be passed on than completely new ones, the team found. This implies that there is a mechanism that filters the mitochondrial DNA when it is being passed down from mother to child, influencing the likelihood that a particular variant becomes established in the human population.

DNA can give us clues to our ancestry – for example, the pattern of genetic variants in an individual’s DNA might be more common in people of European ancestry than it is in people of Asian ancestry. In most people, genetic variants in both our nuclear and mitochondrial DNA come from the same part of the world. However, in around one in 40 people in the UK sample, the mitochondrial DNA and nuclear DNA did not have matching ancestries. For example, the nuclear DNA could be European whilst the mitochondrial DNA is Asian. This happens because at some point in the maternal lineage, there was a mother from a different ethnic background.

“As mitochondrial DNA has a much higher mutation rate than nuclear DNA, mutation of the mitochondrial genome is a common occurrence. We wanted to study the natural selective forces determining the fate of these mutations,” says Dr Ernest Turro of the Department of Haematology and the MRC Biostatistics Unit, and one of the senior authors of this study.

“Our statistical analysis suggests that, in people with differing mitochondrial and nuclear ancestries, recent mitochondrial mutations are more likely to have been seen before in populations with the same nuclear ancestry than the same mitochondrial ancestry.”

Crucially, these results suggest that changes in our mitochondrial DNA are shaped by our nuclear DNA.

“This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand,” says Professor Patrick Chinnery, Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and Wellcome Trust Principal Research Fellow. “What this suggests to us is that swapping mitochondria might not be as straightforward as just changing the batteries in a device.”

̽��ֱ��evidence mirrors that from previous studies in fruit flies and mice, where a mismatch between their mitochondrial and nuclear DNA affected how long the organisms lived for and caused cardiovascular and metabolic complications later in life (diseases in humans that might include heart disease and type 2 diabetes, for example).

̽��ֱ��findings could have implications for mitochondrial donation treatment (also known as mitochondrial replacement therapy), says Professor Chinnery, who previously worked with the team at Newcastle ̽��ֱ�� pioneering this treatment. This technique is now licenced for use in the UK to prevent the transmission from mother to child of potentially devastating mitochondrial diseases. It involves substituting a mother’s nuclear DNA into a donor egg while retaining the donor’s mitochondria.

“Mitochondrial replacement therapy is an important new treatment to enable mothers to have children free from terrible mitochondrial diseases, which arise because of severe mutations in mitochondrial DNA,” says Professor Chinnery.

“Our work suggests we’ll need to look carefully at this new treatment to make sure it does not cause unexpected health problems further down the line. It may mean that doctors will need to match the nuclear genome and mitochondrial genome of mitochondrial donors, similar to an organ transplant.”

̽��ֱ��team has now begun work looking at those people whose mitochondrial DNA does not match their nuclear DNA to see if this mismatch increases the likelihood that they will be affected by health problems later in life.

̽��ֱ��research is the first major population study to arise from data collected as part of the 100,000 Genomes Project, which collects genetic data from patients through the NHS with the aim of transforming the way people are cared for and providing a major new resource for medical research. Pilot data for the study was collected through the NIHR Cambridge Biomedical Research Centre.

“ ̽��ֱ��involvement of the 100,00 Genomes Project in major discoveries demonstrates the importance of large-scale, carefully collected datasets with whole genome sequences, which provide new biological insights and pave the way for major healthcare transformations,” says Professor Mark Caulfield, Chief Executive of Genomics England and Co-Director of the William Harvey Research Institute at Queen Mary ̽��ֱ�� of London.

̽��ֱ��research was largely funded by the NIHR, Wellcome, the MRC and Genomics England.

Reference
Wei, W et al. Germline selection shapes human mitochondrial DNA diversity. Science; 24 May 2019; DOI: 10.1126/science.aau6520

Mitochondria, the ‘batteries’ that produce our energy, interact with the cell’s nucleus in subtle ways previously unseen in humans, according to research published today in the journal Science.

This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand

Patrick Chinnery

Dr David Furness (Wellcome Images)

Three mitochondria surrounded by cytoplasm

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