探花直播 of Cambridge - Department of Genomic Medicine

Cambridge researchers elected to Academy of Medical Sciences Fellowship 2023

lw355 — Thu, 18 May 2023 08:00:52 +0000

探花直播new Fellows have been elected to the Academy in recognition of their exceptional contributions to the advancement of biomedical and health science, cutting-edge research discoveries and translating developments into benefits for patients and wider society.

They join a prestigious Fellowship of 1,400 esteemed researchers who are central to the Academy鈥檚 work. This includes providing career support to the next generation of researchers and contributing to the Academy鈥檚 influential policy work to improve health in the UK and globally.

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

鈥淭his year, we are celebrating our 25th anniversary. 探花直播Fellowship is our greatest asset, and their broad expertise and dynamic ability has shaped the Academy to become the influential, expert voice of health. As we look to the future, the collective wisdom our new Fellows bring will be pivotal in achieving our mission to create an open and progressive research sector to improve the health of people everywhere.鈥�

探花直播new Cambridge Fellows are:

Professor Charlotte Coles FMedSci

Professor of Breast Cancer Clinical Oncology, Department of Oncology, NIHR Research Professor and Director of Cancer Research UK RadNet Cambridge

Professor Coles leads practice-changing breast radiotherapy trials, has influenced international hypofractionation policy and is addressing global health, gender and equity challenges within the Lancet Breast Cancer Commission.

鈥淚t鈥檚 an honour to be elected as a new Fellow of the Academy of Medical Sciences. This is a result of research collaborations in Cambridge, the UK and internationally and I鈥檇 like to thank these wonderful colleagues, especially patient advocates,鈥� said Coles.

鈥淚 hope to contribute to the Academy鈥檚 work to increase equity, diversity and inclusion within leadership roles, including lower- and middle-income countries, to enrich research and improve the culture in Medical Sciences.鈥�

Professor Emanuele Di Angelantonio FMedSci

Professor of Clinical Epidemiology and Donor Health, Department of Public Health and Primary Care, and Head of Health Data Science Centre, Human Technopole (Milan)

Professor Di Angelantonio鈥檚 research has focused on addressing major clinical and public health priorities in cardiovascular disease (CVD) and transfusion medicine. His election recognises his many contributions both in helping resolve important controversies in CVD prevention strategies and in improving the safety and efficiency of blood donation.

鈥淚 am delighted and honoured to be elected to the Fellowship of the Academy of Medical Sciences, which I recognise is an outcome of the collaborations with many colleagues in UK and worldwide,鈥� said Di Angelantonio.

鈥淩esearch excellence across medical sciences and translation to health improvements has been at the centre of the Academy鈥檚 mission and I am very pleased to now be able to contribute to fulfilling this aim as a Fellow.鈥�

Dr Rita Horvath FMedSci

Director of Research in Genetics of Rare Neurological Disorders in the Department of Clinical Neurosciences and Honorary Consultant in Neurology

Dr Horvath is an academic neurologist using genomics and biochemistry to diagnose rare, inherited neurological disorders, with a focus on mitochondrial diseases. Throughout her career she has combined fundamental experimental work with clinical studies. She pioneered the development and implementation of next generation sequencing in the diagnosis of rare neurogenetic diseases in the UK, leading to precision genetic approaches. She has established extensive international collaborations, having impact in Europe, but also for underserved groups in countries where such expertise is lacking.

鈥淚 am delighted and honoured to be elected to this Fellowship, which recognises the impact of my work. I would not have achieved it without the support of my excellent colleagues and research team, for which I give my sincere thanks,鈥� said Horvath.

鈥淎s a Hungarian woman working in different countries before I arrived in the UK in 2007, I feel particularly proud of this award, which I recognise is an outcome of the open and fair research environment in Cambridge. This Fellowship enables me to further expand my research to develop effective treatments for patients with rare inherited neurological diseases.鈥�

Professor Eric Miska FMedSci

Herchel Smith Chair of Molecular Genetics and Head of Department of Biochemistry, Affiliated Senior Group Leader at the Gurdon Institute, Associate Faculty at the Wellcome Sanger Institute and Fellow of St John鈥檚 College

Professor Miska is a molecular geneticist who has carried out pioneering work on RNA biology. His work led to fundamentally new insights into how small RNA molecules control our genes and protect organisms from selfish genes and viruses, and how RNA can carry heritable information across generations. Miska is Founder and Director of STORM Therapeutics Ltd, which creates novel therapies that inhibit RNA modifying enzymes for use in oncology and other diseases.

鈥淲onderful recognition of the work of an amazing team of researchers I have the pleasure to work with,鈥� said Miska. 鈥淢ost of our research has been done using the roundworm C. elegans. As Friedrich Nietzsche wrote in Thus Spoke Zarathustra: 鈥榊ou have evolved from worm to man, but much within you is still worm鈥�.鈥�

Professor Serena Nik-Zainal FMedSci

NIHR Research Professor, Professor of Genomic Medicine and Bioinformatics, Department of Medical Genetics and Early Cancer Institute, and Honorary Fellow of Murray Edwards College

Professor Nik-Zainal鈥檚 research is focused on investigating the vast number of mutations that occur in human DNA from birth, causing patterns called 鈥榤utational signatures鈥�, and the associated physiological changes to cellular function, in progressive diseases such as cancer and neurodegeneration. She uses a combination of experimental and computational methods to understand biology and to develop clinical tests for early detection and precision diagnostics. Her team also builds computational tools to enable genomic advances become more accessible across the NHS.聽

鈥淲hat an honour it is to be elected to the Fellowship. This is a wonderful recognition of the work from my team,鈥� said Nik-Zainal. 鈥淲e are thrilled and hugely indebted to all our inspiring collaborators, supporters and patients, who have shared in our passion and joined us on our path, exploring biomedical science and translating insights into patient benefit.鈥�

Professor Julian Rayner FMedSci

Director of the Cambridge Institute for Medical Research, School of Clinical Medicine, Honorary Faculty at the Wellcome Sanger Institute, and Director of Wellcome Connecting Science

Professor Rayner鈥檚 research has made significant contributions to our understanding of how malaria parasites recognise and invade human red blood cells to cause disease. His work has helped to identify new vaccine targets, such as a protein essential for red blood cell invasion that is now in early stage human vaccine testing, and inform antimalarial drug development, through co-leading the first ever genome-scale functional screens in malaria parasites. He collaborates closely with researchers in malaria-endemic countries and is strongly committed to engaging public audiences with the process and outcomes of science.

鈥淢alaria is a devastating and too often forgotten disease that still kills more than half a million children every year. Tackling it requires deep collaboration and working across disciplines. I鈥檓 enormously honoured by this announcement, which reflects not my work but the work of all the talented people I鈥檝e been lucky enough to host in my lab, and collaborations with friends and colleagues across the world,鈥� said Rayner.

鈥淚鈥檓 excited to become a Fellow of the Academy of Medical Sciences because I strongly share their conviction that science is not just for scientists. I believe that dialogue, learning and public engagement are all fundamental and essential parts of the research process, and I look forward to contributing to their leading role in these areas.鈥�

Professor James Rowe FMedSci

Professor of Cognitive Neurology, Department of Clinical Neurosciences, and MRC Cognition and Brain Sciences Unit

Professor Rowe leads a highly interdisciplinary research team at the Cambridge Centre for Frontotemporal Dementia and at Dementias Platform UK to improve the diagnosis and treatment of people affected by dementia. His work integrates cognitive neuroscience, brain imaging, fluidic biomarkers, computational models and neuropathology for experimental medicine studies and clinical trials. He is motivated by his busy clinical practice and the need for better diversity and inclusivity throughout medical research.

鈥淚 am delighted and honoured to be elected to the Fellowship of the Academy of Medical Sciences. It is a testament to the many wonderful colleagues and students I have been fortunate to work with, and to inspirational mentors,鈥� said Rowe.

鈥淩esearch excellence, and translation of research for direct human benefit, comes from innovation and collaboration in diverse cross-disciplinary teams. I believe in the vision and values of the Academy as the route to better health for all.鈥�

聽

In addition, two researchers from the wider community have also been elected:

Dr Trevor Lawley FMedSci, Senior Group Leader, Wellcome Sanger Institute and Chief Scientific Officer, Microbiotica

Professor Ben Lehner FRS FMedSci, Senior Group Leader, Human Genetics Programme, Wellcome Sanger Institute

Seven Cambridge 探花直播 researchers are among the 59 biomedical and health researchers elected to the Academy of Medical Sciences Fellowship.

As we look to the future, the collective wisdom our new Fellows bring will be pivotal in achieving our mission to create an open and progressive research sector to improve the health of people everywhere

Professor Dame Anne Johnson, President of the Academy of Medical Sciences

Clockwise from top left: E. Di Angelantonio, J. Rayner, J. Rowe, R. Horvath, S. Nik-Zainal, E. Miska, C. Coles

探花直播text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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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探花直播doctor turned detective investigating the imprints of cancer

cg605 — Mon, 15 Aug 2022 12:56:04 +0000

Self-confessed 鈥榥erd鈥� Serena Nik-Zainal went from hospital wards to the laboratory on a mission to provide patients with the best possible treatment for their illnesses. Ten years later she is at the forefront of genomic research, creating tools for clinicians which are transforming patient care.

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

cjb250 — Thu, 11 Aug 2022 15:00:32 +0000

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鈥檚.

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 探花直播 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 billion 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 鈥� a letter C might change to a letter T, for example. 鈥楩ingerprints鈥� 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, who carried out the work while at the 探花直播 of Cambridge and the Wellcome Sanger Institute, said: 鈥淲e 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. 探花直播most striking thing was that pairs of iPS cells would have a vastly different genetic landscape 鈥� 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.鈥�

探花直播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 from the Department of Medical Genetics at the 探花直播 of Cambridge said: 鈥淎lmost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations 鈥� sometimes more than we find in tumours.聽 We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people.鈥�

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: 鈥淲hat we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations 鈥� 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.鈥�

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 鈥� 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.

鈥� 探花直播DNA damage that we saw was at a nucleotide level,鈥� says Professor Nik-Zainal. 鈥淚f 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.鈥�

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.

鈥� 探花直播cost of whole genome sequencing has dropped dramatically in recent years to around 拢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.鈥�

Dr Rouhani adds: 鈥淚n 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. 探花直播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.

鈥淚f 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.鈥�

探花直播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.

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

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.

Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations 鈥� sometimes more than we find in tumours

Serena Nik-Zainal

Alexas_Fotos

Sun

探花直播text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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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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 探花直播 of Cambridge, 探花直播 College London and Cardiff 探花直播 established IMAGINE ID, a national UK cohort study that aims to discover how genetic changes affect children and young people鈥檚 behaviour, in order to inform better care of families and children now and in the future.

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

Professor Lucy Raymond from the 探花直播 of Cambridge, the study鈥檚 senior author, said: 鈥淭hanks to all the families that have taken part in our research, we鈥檝e been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability. What we鈥檝e 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.鈥�

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 鈥� a so-called copy number variant (CNV). 探花直播remaining young people had a disability caused by a single 鈥榮pelling error鈥� in their DNA 鈥� a change in the A, C, G or T nucleotides 鈥� 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 鈥� 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, 探花直播 College London, said: 鈥淩outine 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鈥檚 future mental health.

鈥淲e 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.鈥�

探花直播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, 探花直播 College London, said: 鈥淲e hope this work helps improve the targeting of assessments and interventions to support families at the earliest opportunity. We鈥檇 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.鈥�

探花直播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 - 探花直播UK National Cohort Study. Lancet Psychiatry; 4 Aug 2022; DOI: 10.1016/PIIS2215-0366(22)00207-3

聽

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鈥檝e 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

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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 探花直播 Hospitals (CUH) and the 探花直播 of Cambridge, analysed the complete genetic make-up or whole-genome sequences (WGS) of more than 12,000 NHS cancer patients.聽聽

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 鈥榤utational signatures鈥�, 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.

探花直播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. 探花直播results are reported in the journal Science.

探花直播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.

鈥淲GS gives us a total picture of all the mutations that have contributed to each person鈥檚 cancer,鈥� said first author Dr Andrea Degasperi, from Cambridge鈥檚 Department of Oncology. 鈥淲ith 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.鈥�

鈥� 探花直播reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene - they help to pinpoint cancer culprits,鈥� said Serena Nik-Zainal, from the Department of Medical Genetics and an honorary consultant in clinical genetics at CUH. 鈥淪ome mutational signatures have clinical or treatment implications 鈥� they can highlight abnormalities that may be targeted with specific drugs or may indicate a potential 鈥楢chilles heel鈥� in individual cancers.

鈥淲e 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.聽 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.鈥�

Michelle Mitchell, chief executive of Cancer Research UK, which funded the research, said:

鈥淭his 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.鈥�

Professor Matt Brown, chief scientific officer of Genomics England said:

鈥淢utational signatures are an example of using the full potential of WGS.聽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.鈥�

Professor Dame Sue Hill, chief scientific officer for England and Senior Responsible Officer for Genomics in the NHS said:

鈥� 探花直播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.鈥�

Reference:
Andrea Degasperi et al. 鈥�Substitution mutational signatures in whole-genome鈥搒equenced cancers in the UK population.鈥� 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 鈥榯reasure trove鈥� 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.

探花直播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

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Faulty BRCA genes linked to prostate and pancreatic cancers

cjb250 — Tue, 25 Jan 2022 21:00:40 +0000

A study published today in the Journal of Clinical Oncology has provided the strongest evidence to date of these links and helped researchers estimate more accurately the associated risk.

Since these genes were discovered in the mid 90s, numerous studies have explored possible links between BRCA1 and BRCA2 mutations and other cancers. However, these studies had small sample sizes, resulting in imprecise estimates of cancer risk. Being able to estimate the risks accurately is important for informing cancer prevention and screening strategies and providing genetic counselling to those at greatest risk. BRCA mutations are uncommon, affecting around 1 in 300-400 people in the population.

To further investigate these risk estimates, a team led by researchers at the 探花直播 of Cambridge, funded by Cancer Research UK, analysed data from almost 3,200 families with one or more members with the BRCA1 mutation and almost 2,200 families with members carrying the BRCA2 mutation. 探花直播families had all been recruited to the Consortium of Investigators of Modi铿乪rs of BRCA1/2. 探花直播researchers examined the associations with 22 primary cancers.

From the data, the researchers estimated that men who carry a BRCA2 mutation have a 27% risk of developing prostate cancer by the time they are 80 years old, more than double the rate compared to non-carriers. BRCA1 mutations were not associated with an increase in prostate cancer risk.

Carrying a defective copy of either BRCA1 or BRCA2 more than doubled an individual鈥檚 risk of pancreatic cancer to 2.5-3% by age 80.

探花直播mutations were also found to increase the risk of stomach cancer, though the researchers caution that because of the rarity of this form of cancer, the number of patients in their datasets was small.

Mutations in both genes significantly increased the risk of breast cancer in men, though the disease is still very rare, accounting for less than 1% of all male cancer cases in the UK. While a BRCA1 mutation increased a man鈥檚 risk of developing breast cancer more than four-fold to 0.4% by age 80, a BRCA2 mutation increased this risk by 44 times to 3.8% by age 80. It is estimated that 38 out of 1,000 male carriers of the BRCA2 mutation will develop breast cancer by age 80.

探花直播researchers were unable to find compelling evidence that mutations were linked to increased risk of some other cancers which were previously thought to be linked to faulty BRCA genes, such as melanoma.

Cancer Research UK says that people who are worried about their risk of cancer should talk to their GP. GPs can refer patients to a genetics clinic if they think someone has a strong family history and might be at an increased risk.

Professor Antonis Antoniou from the Department of Public Health and Primary Care at the 探花直播 of Cambridge, who led the research, said: 鈥淭hese large datasets of patients have allowed us to estimate with much greater accuracy the extent to which faulty BRCA1 and BRCA2 genes increase the risk of several cancers. We鈥檝e known for some time that they鈥檙e linked to breast and ovarian cancer, but there鈥檚 been uncertainty about other cancers.鈥�

Professor Marc Tischkowitz from the Department of Medical Genetics at the 探花直播 of Cambridge added: 鈥� 探花直播link between BRCA2 and prostate cancer and pancreatic cancer is now much clearer, thanks to the data we鈥檝e analysed. We have also identified a potential link with stomach cancer, but this is based on small numbers and needs further study. Our data suggests that there is no strong link between BRCA2 and melanoma, which may provide greater clarity to BRCA2 gene carriers.

鈥淥verall, the results will add to our knowledge on optimising cancer screening and early detection strategies for people who are known to carry these faulty genes.鈥�

Michelle Mitchell, Chief Executive of Cancer Research UK, said: 鈥淥ur scientists helped to discover BRCA over 25 years ago and established that faults in these genes increase breast cancer risk. This study has built on that vital knowledge, giving us some important new insights into BRCA genes and the likely risks of developing prostate and pancreatic cancer.

鈥淐ancers caused by inherited faulty BRCA genes are relatively rare, and other factors like age, smoking, diet and other preventable factors contribute to a person鈥檚 risk.

鈥淚mproving our understanding of how faults in our genes are associated with certain cancers puts us in a much better position to pinpoint those at a higher risk of developing cancer.鈥� 聽

Reference
Li, S et al. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Journal of Clinical Oncology; 25 Jan 2022; DOI: 10.1200/JCO.21.02112

Faulty versions of the BRCA1 and BRCA2 genes are well known to increase the risk of breast cancer in men and women, and in ovarian cancer. Now BRCA1 and BRCA2 have been linked to several other cancers, including those that affect men.

These large datasets of patients have allowed us to estimate with much greater accuracy the extent to which faulty BRCA1 and BRCA2 genes increase the risk of several cancers

Antonis Antoniou

KATERYNA KON/SCIENCE PHOTO LIBRARY

Prostate cancer cells

Yes

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 鈥� the NHS.

探花直播study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the 探花直播 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 鈥� aged 0 to 92 with a median age of 25 years 鈥� 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 探花直播 of Cambridge, said:

鈥淲e 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鈥檛 need to travel long distances to multiple appointments, and they would get their diagnosis much faster.鈥�

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

鈥淎 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.鈥�

探花直播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. 探花直播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. 探花直播study offers a valuable new resource for the discovery of future mitochondrial disease genes.

探花直播majority of the team鈥檚 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: 鈥淭hese 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鈥檛 restricted by that bias.鈥�

A small number of newly diagnosed participants are already receiving treatments as a result. 探花直播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: 鈥淒iagnostic 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: 鈥淚f 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.鈥�

探花直播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:

鈥淲e 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.鈥�

Reference

KR Schon et al., 鈥�Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study鈥�, 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 鈥榙iagnostic odyssey鈥� 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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No deal Brexit could have detrimental impact for four million people in UK living with a rare disease

cjb250 — Fri, 11 Dec 2020 23:30:12 +0000

One in 17 UK citizens lives with a rare disease, which are defined as conditions that affect fewer than one in 2,000 people in the general population. A group of experts has written to 探花直播Lancet highlighting their concerns about the detrimental impact a no deal Brexit will have on these individuals.

鈥淩are diseases are rare, and experts are rarer still,鈥� said Dr Marc Tischkowitz from the 探花直播 of Cambridge, who helped coordinate the letter. 鈥淓uropean Reference Networks were set up because no single country has the expertise or resources to cover all of the known rare diseases, which number in the thousands. They鈥檝e played a pivotal role in harnessing the collective knowledge across the continent and in developing sustainable healthcare to treat those affected.鈥�

探花直播UK has been at the forefront of the creation and development of these virtual networks, which involve healthcare providers across Europe. As a result, write the experts, it has been able 鈥渢o reap the benefits of closer collaboration with experts and patient advocates throughout Europe鈥�.

探花直播ERNs have made it much easier to develop guidelines, create disease registries, build research collaborations, and create new education and training programmes. Crucially, they have directly improved patient care by establishing a pan-European platform that brings international experts together to advise on patient-specific complex problem and therapeutic options where insufficient expertise exists in one country alone.

Dr Tischkowitz added: 鈥淟eaving the EU without an agreement on UK participation in the Networks means we potentially write off years of progress made by UK clinicians, researchers and patient advocates, while also reducing access to clinical trials and funding. Most importantly, it will diminish our ability to provide the best care for the millions of children and adults with rare diseases and complex conditions in the future.鈥�

探花直播letter has a total of 73 signatories, including 20 signatories each representing a patient support group and 53 signatories from senior clinicians and researchers who are currently members of a European Reference Network and who will be removed from the networks as of 1 January if no agreement is reached.

Allison Watson co-founded Ring20, a charity that supports people living with ring chromosome 20 Syndrome, an ultra-rare disease that affects her young adult son. She is also a co-lead for the EpiCARE ERN for rare and complex epilepsies.

鈥淚 have been hugely encouraged by the change that being part of an ERN can bring, for people like my son and many others living with ultra-rare diseases,鈥� said Watson. 鈥淚 believe we would not have managed this working with just UK rare disease organisations.鈥�

Initiatives already delivered through the EpiCARE ERN include heightened awareness of rare epilepsies (including ring chromosome 20 Syndrome) across the 28 EpiCARE centres, long overdue Orphanet updates, increased information and education to healthcare practitioners and patient families in the form of leaflets and patient journeys, plus updated Clinical Practice Guidelines which aim to simplify and speed up diagnosis and improve care through understanding the unmet needs.

Watson added: 鈥淲ith thousands of rare diseases, many of them ultra-rare where only a handful of people living in the UK are affected, is it cost-effective or even possible that the UK can deliver effective services and research alone for these people alone? I believe only through collaboration with our European partners and others around the world can we truly meet the needs of the affected and ultimately improve their outcomes and quality of life.鈥�

Beverley Power, chair of CDH UK, the congenital diaphragmatic hernia support charity, says that one of the main barriers to research within the field of rare diseases is access to patients and patient data.

鈥淪ince joining the ERNICA European Reference Network, the access to patients and data has become broader for the UK and the rest of Europe,鈥� she explained. 鈥淚t has enabled charities like CDH UK to better understand other healthcare settings and to be able to signpost newly diagnosed parents and patients with ongoing聽medical needs in a much better direction. It has also introduced new and innovative ways to collaborate in order to effect better outcomes and quality of life for patients and their families, which ultimately can potentially impact the economic聽implications of treating rare diseases in the UK and overseas.鈥�

Reference
Tischkowitz, M et al. A no-deal Brexit will be detrimental to people with rare diseases. Lancet; 12 Dec 2020; DOI: 10.1016/S0140-6736(20)32631-3

Correspondence pieces represent the views of the authors and not necessarily the views of 探花直播Lancet or any Lancet specialty journal. Unlike Articles containing original research, this Correspondence was not externally peer reviewed.

Experts have warned that a 鈥榥o deal鈥� Brexit will result in the exclusion of the UK from the 24 European Reference Networks (ERNs) that were established to improve the care of patients bearing the lifelong burden of a rare disease, which require highly specialised diagnosis and treatment.

Rare diseases are rare, and experts are rarer still. European Reference Networks were set up because no single country has the expertise or resources to cover all of the known rare diseases, which number in the thousands

Mark Tischkowitz

Tumisu

Brexit

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