̽��ֱ�� of Cambridge - Nicole Soranzo

Role of inherited genetic variants in rare blood cancer uncovered

jg533 — Wed, 17 Jan 2024 10:03:16 +0000

Large-scale genetic analysis has helped researchers uncover the interplay between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

Researchers from the ̽��ֱ�� of Cambridge, Wellcome Sanger Institute, and collaborators, combined various comprehensive data sets to understand the impact of both cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

̽��ֱ��study, published in the journal Nature Genetics, describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

This analysis has an impact on current clinical predictions of disease development in individuals. Further research is required to understand the biological mechanisms behind how these inherited genetic variants influence the chances of developing rare blood cancer. In the future, this knowledge could aid drug development and interventions that reduce the risk of disease.

Myeloproliferative neoplasms, MPNs, are a group of rare, chronic, blood cancers. There are around 4,000 cases of MPN in the UK each year. These occur when the bone marrow overproduces blood cells, which can result in blood clots and bleeding. MPNs can also progress into other forms of blood cancer, such as leukaemia.

In the population, there is a large amount of natural variation between individuals’ blood cells, which can affect the amount of blood cells a person has and their particular traits. This is because multiple different genes can influence blood cell features in an individual. During routine blood tests, researchers take known information about these genes and analyse the variation to give a genetic risk score, which is how likely that individual is to develop a disease over their lifetime.

MPNs have been linked to random somatic mutations in certain genes including in a gene called JAK2. However, mutated JAK2 is commonly found in the global population, and the vast majority of these individuals do not have or go on to develop MPN.

Whilst previous studies have identified over a dozen associated inherited genetic variants that increase the risk of MPN, these studies insufficiently explain why most individuals in the population do not go on to develop MPN.

This new study, from the Wellcome Sanger Institute and collaborators, combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will go on to cause MPN. They also found that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, thus, mimicking disease.

Dr Jing Guo, from the ̽��ֱ�� of Cambridge and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk. By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

Professor Nicole Soranzo, co-senior author from the ̽��ֱ�� of Cambridge, the Wellcome Sanger Institute, and Human Technopole, Italy, said: “There has been increasing realisation that human diseases have complex causes involving a combination of common and rare inherited genetic variants with different severity.

“We have previously shown that variation in blood cell parameters and function has complex genetic variability by highlighting thousands of genetic changes that affect different gene functions. Here, we show for the first time that common variants in these genes also affect blood cancers, independent of causative somatic mutations. This confirms a new important contribution of normal variability beyond complex disease, contributing to our understanding of myeloproliferative neoplasms and blood cancer more generally.”

Dr Jyoti Nangalia, co-senior author from the Wellcome-MRC Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge, and the Wellcome Sanger Institute, said: “We have a good understanding of the genetic causes of myeloproliferative neoplasms. In fact, many of these genetic mutations are routine diagnostic tests in the clinic. However, these mutations can often be found in healthy individuals without the disease.

“Our study helps us understand how inherited DNA variation from person to person can interact with cancer-causing mutations to determine whether disease occurs in the first place, and how this can alter the type of any subsequent disease that emerges. Our hope is that this information can be incorporated into future disease prediction efforts.”

This research was funded by Cancer Research UK and Wellcome.

Reference

J Guo, K Walter, P M Quiros, et al. ‘Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.’ Jan 2024, Nature Genetics. DOI: 10.1038/s41588-023-01638-x

Adapted from a press release by the Wellcome Sanger Institute

Combining three different sources of genetic information has allowed researchers to further understand why only some people with a common mutation go on to develop rare blood cancer.

Our hope is that this information can be incorporated into future disease prediction efforts

Jyoti Nangalia

Photo by Sangharsh Lohakare on Unsplash

DNA

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Cambridge scientists recognised by major European research organisation

cjb250 — Tue, 18 Jun 2019 11:42:19 +0000

Cambridge ̽��ֱ�� has the highest number of new members of any institution within Europe. Five ̽��ֱ�� of Cambridge researchers are among the 48 scientists from 17 countries elected:

Professor Sadaf Farooqi – Wellcome-Medical Research Council (MRC) Institute of Metabolic Science
Dr Fanni Gergely – Cancer Research UK Cambridge Institute
Professor Paul Lehner – Department of Medicine and the Cambridge Institute for Medical Research
Professor Lalita Ramakrishnan – Department of Medicine and the MRC Laboratory of Molecular Biology
Professor Nicole Soranzo – Department of Haematology and Wellcome Sanger Institute

In addition, Dr Garib Murshudov from the MRC Laboratory of Molecular Biology has also been elected.

EMBO is an organisation of more than 1800 leading researchers in Europe and around the world, whose mission is to promote excellence in the life sciences in Europe and beyond. ̽��ֱ��major goals of the organisation are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information and help build a research environment where scientists can achieve their best work.

“EMBO Members are excellent scientists who conduct research at the forefront of all life science disciplines, ranging from computational models or analyses of single molecules and cellular mechanics to the study of higher-order systems in development, cognitive neuroscience and evolution,” says EMBO Director Maria Leptin.

“We’re very honoured to have been elected as members of EMBO,” says Professor Farooqi. “This is great recognition for the excellent science taking place across our city, particularly on the Cambridge Biomedical Campus. We are proud of the role we play in European science and look forward to continuing to work in partnership with colleagues across the continent.”

Researchers from the Cambridge Biomedical Campus have featured prominently in this year’s election to the prestigious European Molecular Biology Organisation (EMBO).

We are proud of the role we play in European science and look forward to continuing to work in partnership with colleagues across the continent

Sadaf Farooqi

CDC/ Melissa Brower

This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of rod-shaped drug-resistant Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB).

̽��ֱ��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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Fake news, black holes and AI: Cambridge academics to speak at Hay Festival

mjg209 — Tue, 26 Mar 2019 11:00:00 +0000

̽��ֱ��Series is now an established feature of the Hay Festival and is now in its eleventh year. This year’s speakers include experts on the localised effects of climate change, combatting fake news, black holes, food security and the impact of dinosaurs on the British landscape.

̽��ֱ��Series is part of the ̽��ֱ�� of Cambridge’s commitment to public engagement. ̽��ֱ��Festival runs from 25th May to 2nd June and is now open for bookings.

Several speakers will address how experts navigate a world of fake news and artificial intelligence. Bill Sutherland, Miriam Rothschild Chair in Conservation Biology, will describe attempts to make global evidence available to all, improve the effectiveness of experts and change attitudes toward the use of evidence, especially in relation to conservation. Sander van der Linden from the Cambridge Social Decision-Making Lab and Department of Psychology will speak about how we can counter fake news and whether we can inoculate the public against misinformation. His forthcoming book will investigate the psychology of trust and how to communicate about facts and evidence in a post-truth society. Rapid changes in the use of artificial intelligence and the social and ethical implications of these will be discussed by Adrian Weller, a senior research fellow in machine learning.

Other speakers will address how reading is being transformed in a digital age. Writer, editor and researcher Tyler Shores will explore reading in an age of digital distraction while literacy education expert Fiona Maine will speak about the potential of complex, ambiguous wordless picturebooks and short films as springboards for children’s critical and creative discussions about the world and how we live in it.

From the world of science speakers include Professor Nicole Soranzo on the evolution of human genetics and how new genetic evidence is being used to better understand the interplay between our DNA (‘nature’) and the environment (‘nurture’). Professor Christopher Reynolds will describe how black holes stretch our understanding of space-time to the limits and power some of the most energetic phenomena in the Universe. Neuroscientist Professor Paul Fletcher will explain how different processes in the brain can lead to seemingly irrational decisions when it comes to what we eat. Dr Catherine Aitken will explore how life in the womb affects not only children’s lifelong health and well-being, but maybe even that of grandchildren.

Responses to climate change feature in several Cambridge Series sessions: climate change scientist Emily Shuckburgh will speak about her research on modelling localised effects of climate change and will also be in conversation with former Irish president Mary Robinson about climate justice. Another Cambridge Series session on female voices on climate change will see a panel of researchers talk about what kind of adaptations may be required as global warming increases and how we bring a broad range of the public on board, particularly with regard to the more complex issues around climate change. Speakers include Chandrika Nath, executive director of the Scientific Committee on Antarctic Research, Professor Melody Clark from the British Antarctic Survey and two Gates Cambridge Scholars - Morgan Seag, co-chair of the international council of the Association of Polar Early Career Scientists, and anthropologist Ragnhild Freng Dale from the Scott Polar Research Institute and the Western Norway Research Institute.

Other sessions explore issues of identity. Professor Michael Kenny will take part in a panel discussion on Brexit and the politics of national identity in the UK with Welsh government minister Eluned Morgan and Adam Price, leader of Plaid Cymru, while economist Victoria Bateman will address the role of women in the economic rise of the West. Her new book ̽��ֱ��Sex Factor - how women made the West rich argues that, far from the Industrial Revolution being all about male inventors and industrialists, the everyday woman underpinned Britain’s – and the West’s - rise.

For those interested in the more distant past Anthony Shillito and Neil Davies will explore their research on how ancient creatures, from dinosaurs to giant millipedes, shaped the land around them and what secrets are held within their prehistoric footprints. Martin Jones, Emeritus Professor of Archaeological Science at the ̽��ֱ�� of Cambridge, will discuss the vital question of food security, showing how our prehistoric ancestors built resilience into their food supply and what we can learn from them.

Peter Florence, director of Hay Festival, said: "Cambridge ̽��ֱ�� is home to some of the world's greatest thinkers, at the forefront of debate and exploration in the arts, sciences and global affairs. We're proud to open those ideas into conversations that resonate around the world from our field in Wales. Join us."

Ariel Retik, who oversees the Cambridge Series, said: “We are proud to continue our valued relationship with Hay. ̽��ֱ��Festival is a wonderful way of sharing with the public the research and learning that happens in Cambridge. We have found that Hay audiences are diverse, engaged and intellectually curious. They are an incredible cross-section of the public: from potential students and tourists, to journalists and policy-makers – everyone is represented. They are always interested in the research and, importantly, ask fantastic and challenging questions! We are excited for another year of talks and debates around the research and emerging ideas from Cambridge, which have global relevance and potential for world-changing impact."

Other ̽��ֱ�� of Cambridge speakers at the Festival include Professor Martin Rees, neuroscientist Giles Yeo, author and lecturer Robert Macfarlane and neuroscientist Hannah Critchlow. Charlie Gilderdale, NRICH Project Secondary Coordinator, will once again be running maths masterclasses with Alison Eves from the Royal Institution.

Book tickets

Full line-up of the Cambridge Series

Nineteen academics from a wide range of disciplines will take part in this year’s Cambridge Series of talks at the Hay Festival, one of the most prestigious literary festivals in the world.

We are excited for another year of talks and debates around the research and emerging ideas from Cambridge, which have global relevance and potential for world-changing impact

Ariel Retik

Sam Hardwick

Hay Festival

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Academy of Medical Sciences announces 2018 Fellowships

cjb250 — Thu, 10 May 2018 10:22:09 +0000

̽��ֱ��new Fellows have been elected for their outstanding contributions to biomedical and health science, leading research discoveries, and translating developments into benefits for patients and the wider society.

This year's elected Fellows have expertise that spans sleep research, infectious and tropical diseases, diabetes medicine, parasite biology and ultrasound research and technology among many other fields.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: “ ̽��ֱ��Academy simply could not tackle major health and policy challenges without our dynamic and diligent brain trust of Fellows. I extend my warmest congratulations to all who are joining us this year, each of whom has earnt this prestige by advancing their own field of biomedical science.

“Later this year the Academy will celebrate 20 years of supporting the translation of biomedical and health research into benefits for society. As we celebrate this special anniversary we stand at a crossroads of both enormous health challenges and great opportunity for medical sciences. So I am delighted to see the remarkable breadth and depth of the expertise within our 48 new Fellows. We look forward to these experts joining us in addressing the health challenges we face head on and exploiting opportunities to improve health in the UK and internationally.”

̽��ֱ��Cambridge researchers among the new Fellows are:

Professor Simon Baron-Cohen FBA, Autism Research Centre
Professor Simon Griffin, Department of Public Health and Primary Care
Professor James Huntington, Cambridge Institute for Medical Research
Professor Peter Hutchinson, Department of Clinical Neurosciences
Professor Jonathan Mant, Department of Public Health and Primary Care
Professor Lalita Ramakrishnan, Department of Medicine
Professor David Rowitch, Department of Paediatrics
Professor Nicole Soranzo, Department of Haematology

̽��ֱ��new Fellows will be formally admitted to the Academy at a ceremony on 27 June 2018.

Eight Cambridge academics are among 48 of the UK’s world leading researchers who have been elected to join the prestigious Fellowship of the Academy of Medical Sciences.

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A BLUEPRINT for blood cells: Cambridge researchers play leading role in major release of epigenetic studies

cjb250 — Thu, 17 Nov 2016 17:00:15 +0000

̽��ֱ��studies are part of BLUEPRINT, a large-scale research project bringing together 42 leading European universities, research institutes and industry entrepreneurs, with close to €30 million of funding from the EU. BLUEPRINT scientists have this week released a collection of 26 publications, part of a package of 41 publications being released by the International Human Epigenome Consortium.

One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single stem cell and how information encoded in different parts of our genome are made available to be used by different cell types. Scientists have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. ̽��ֱ��identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome – the epigenome – which acts as a blueprint unique to each cell type and developmental stage.

Unlike the genome, the epigenome changes as cells develop and in response to changes in the environment. Defects in the proteins that read, write and erase the epigenetic information are involved in many diseases. ̽��ֱ��comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes.

“This huge release of research papers will help transform our understanding of blood-related and autoimmune diseases,” says Professor Willem H Ouwehand from the Department of Haematology at the ̽��ֱ�� of Cambridge, one of the Principal Investigators of BLUEPRINT. “BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health.”

Among the papers led by Cambridge researchers, Professor Nicole Soranzo and Dr Adam Butterworth have co-led a study analysing the effect of genetic variants in our DNA sequence on our blood cells. Using a genome-wide association analysis, the team identified more than 2,700 variants that affect blood cells, including hundreds of rare genetic variants that have far larger effects on the formation of blood cells than the common ones. Interestingly, they found genetic links between the effects of these variants and autoimmune diseases, schizophrenia and coronary heart disease, thereby providing new insights into the causes of these diseases.

A second study led by Professor Soranzo looked at the contribution of genetic and epigenetic factors to different immune cell characteristics in the largest cohort of this kind created with blood donors from the NHS Blood and Transplant centre in Cambridge.

Dr Mattia Frontini and Dr Chris Wallace, together with scientists at the Babraham Institute, have jointly led a third study mapping the regions of the genome that interact with genes in 17 different blood cell types. By creating an atlas of links between genes and the remote regions that regulate them in each cell type, they have been able to uncover thousands of genes affected by DNA modifications, pointing to their roles in diseases such as rheumatoid arthritis and other types of autoimmune disease.

Dr Frontini has also co-led a study with BLUEPRINT colleagues from the ̽��ֱ�� of Vienna that has developed a reference map of how epigenetic changes to DNA can program haematopoietic stem cells – a particular type of ‘master cell’ – to develop into the different types of blood and immune cells.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the research, said: “Our genes are critical to our health and there’s still a wealth of information hidden in our genetic code. By taking advantage of a large scale international collaboration, involving the combined expertise of dozens of research groups, these unprecedented studies have uncovered potentially crucial knowledge for the development of new life saving treatments for heart disease and many other deadly conditions.

“Collaborations like this, which rely on funding from the public through charities and governments across the globe, are vital for analysing and understanding the secrets of our genetics. Research of this kind is helping us to beat disease and improve millions of lives.”

Departmental Affiliations

Professor Nicole Soranzo – Department of Haematology
Dr Adam Butterworth – Medical Research Council (MRC)/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit
Dr Mattia Frontini – Department of Haematology, and Senior Research Fellow for the BHF Cambridge Centre for Research Excellence
Dr Chris Wallace – Department of Medicine and MRC Biostatistics Unit

References

Astle, WJ et al. ̽��ֱ��allelic landscape of human blood cell trait variation. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.10.042
Chen, L et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell; 17 Nov 2016; DOI: 10.1371/journal.pbio.0000051
Javierre et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.09.037
Farlik et al. Cell Stem Cell; 17 Nov 2016; DOI: 10.1016/j.stem.2016.10.019

Cambridge researchers have played a leading role in several studies released today looking at how variation in and potentially heritable changes to our DNA, known as epigenetic modifications, affect blood and immune cells, and how this can lead to disease.

BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health

Willem Ouwehand

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Detail of Epigenome

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