̽��ֱ�� of Cambridge - Serena Nik-Zainal

Scientists create 'metal detector' to hunt down tumours

cjb250 — Thu, 10 Apr 2025 09:00:56 +0000

In a paper published today in Nature Genetics, scientists at the ̽��ֱ�� of Cambridge and NIHR Cambridge Biomedical Research Centre analysed the full DNA sequence of 4,775 tumours from seven types of cancer. They used that data from Genomics England’s 100,000 Genomes Project to create an algorithm capable of identifying tumours with faults in their DNA that makes them easier to treat.

̽��ֱ��algorithm, called PRRDetect, could one day help doctors work out which patients are more likely to have successful treatment. That could pave the way for more personalised treatment plans that increase people’s chances of survival.

̽��ֱ��research was funded by Cancer Research UK and the National Institute for Health and Care Research (NIHR).

Professor Serena Nik-Zainal from the Early Cancer Institute at the ̽��ֱ�� of Cambridge, lead author of the study, said: “Genomic sequencing is now far faster and cheaper than ever before. We are getting closer to the point where getting your tumour sequenced will be as routine as a scan or blood test.

“To use genomics most effectively in the clinic, we need tools which give us meaningful information about how a person’s tumour might respond to treatment. This is especially important in cancers where survival is poorer, like lung cancer and brain tumours.

“Cancers with faulty DNA repair are more likely to be treated successfully. PRRDetect helps us better identify those cancers and, as we sequence more and more cancers routinely in the clinic, it could ultimately help doctors better tailor treatments to individual patients.”

̽��ֱ��research team looked for patterns in DNA created by so-called ‘indel’ mutations, in which letters are inserted or deleted from the normal DNA sequence.

They found unusual patterns of indel mutations in cancers that had faulty DNA repair mechanisms – known as ‘post-replicative repair dysfunction’ or PRRd. Using this information, the scientists developed PRRDetect to allow them to identify tumours with this fault from a full DNA sequence.

PRRd tumours are more sensitive to immunotherapy, a type of cancer treatment that uses the body’s own immune system to attack cancer cells. ̽��ֱ��scientists hope that the PRRd algorithm could act like a ‘metal detector’ to allow them to identify patients who are more likely to have successful treatment with immunotherapy.

̽��ֱ��study follows from a previous ‘archaeological dig’ of cancer genomes carried out by Professor Nik-Zainal, which examined the genomes of tens of thousands of people and revealed previously unseen patterns of mutations which are linked to cancer.

This time, Professor Nik-Zainal and her team looked at cancers which have a higher proportion of tumours with PRRd. These include bowel, brain, endometrial, skin, lung, bladder and stomach cancers. Whole genome sequences of these cancers were provided by the 100,000 Genomes Project - a pioneering study led by Genomics England and NHS England which sequenced 100,000 genomes from around 85,000 NHS patients affected by rare diseases or cancer.

̽��ֱ��study identified 37 different patterns of indel mutations across the seven cancer types included in this study. Ten of these patterns were already linked to known causes of cancer, such as smoking and exposure to UV light. Eight of these patterns were linked to PRRd. ̽��ֱ��remaining 19 patterns were new and could be linked to causes of cancer that are not fully understood yet or mechanisms within cells that can go wrong when a cell becomes cancerous.

Executive Director of Research and Innovation at Cancer Research UK, Dr Iain Foulkes, said: “Genomic medicine will revolutionise how we approach cancer treatment. We can now get full readouts of tumour DNA much more easily, and with that comes a wealth of information about how an individual’s cancer can start, grow and spread.

“Tools like PRRDetect are going to make personalised treatment for cancer a reality for many more patients in the future. Personalising treatment is much more likely to be successful, ensuring more people can live longer, better lives free from the fear of cancer.”

NIHR Scientific Director, Mike Lewis, said: “Cancer is a leading cause of death in the UK so it's impressive to see our research lead to the creation of a tool to determine which therapy will lead to a higher likelihood of successful cancer treatment.”

Chief Scientific Officer at Genomics England, Professor Matt Brown, said: “Genomics is playing an increasingly important role in healthcare and these findings show how genomic data can be used to drive more predictive, preventative care leading to better outcomes for patients with cancer.

“ ̽��ֱ��creation of this algorithm showcases the immense value of whole genome sequencing not only in research but also in the clinic across multiple diverse cancer types in advancing cancer care.”

̽��ֱ�� ̽��ֱ�� of Cambridge is fundraising for a new hospital that will transform how we diagnose and treat cancer. Cambridge Cancer Research Hospital, a partnership with Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, will treat patients across the East of England, but the research that takes place there promises to change the lives of cancer patients across the UK and beyond. Find out more here.

Reference

Koh, GCC et al. Redefined indel taxonomy reveals insights into mutational signatures. Nat Gen; 10 Apr 2025; DOI:

Adapted from a press release from Cancer Research UK

Cambridge researchers have created a ‘metal detector’ algorithm that can hunt down vulnerable tumours, in a development that could one day revolutionise the treatment of cancer.

Genomic sequencing is now far faster and cheaper than ever before. We are getting closer to the point where getting your tumour sequenced will be as routine as a scan or blood test

Professor Serena Nik-Zainal

̽��ֱ�� of Cambridge

Serena Nik-Zainal at the Early Cancer Institute

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

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Inside the institute looking at early cancer

cjb250 — Wed, 24 Jul 2024 07:00:47 +0000

Today sees the launch of the Early Cancer Institute at Cambridge. Its mission is deceptively simple: to detect cancer early enough to cure it.

Cambridge researchers elected to Academy of Medical Sciences Fellowship 2023

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

̽��ֱ��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’s work. This includes providing career support to the next generation of researchers and contributing to the Academy’s influential policy work to improve health in the UK and globally.

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

“This year, we are celebrating our 25th anniversary. ̽��ֱ��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.”

̽��ֱ��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.

“It’s 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’d like to thank these wonderful colleagues, especially patient advocates,” said Coles.

“I hope to contribute to the Academy’s 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.”

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’s 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.

“I 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,” said Di Angelantonio.

“Research excellence across medical sciences and translation to health improvements has been at the centre of the Academy’s mission and I am very pleased to now be able to contribute to fulfilling this aim as a Fellow.”

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.

“I 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,” said Horvath.

“As 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.”

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’s 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.

“Wonderful recognition of the work of an amazing team of researchers I have the pleasure to work with,” said Miska. “Most of our research has been done using the roundworm C. elegans. As Friedrich Nietzsche wrote in Thus Spoke Zarathustra: ‘You have evolved from worm to man, but much within you is still worm’.”

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’s research is focused on investigating the vast number of mutations that occur in human DNA from birth, causing patterns called ‘mutational signatures’, 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.

“What an honour it is to be elected to the Fellowship. This is a wonderful recognition of the work from my team,” said Nik-Zainal. “We 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.”

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’s 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.

“Malaria 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’m enormously honoured by this announcement, which reflects not my work but the work of all the talented people I’ve been lucky enough to host in my lab, and collaborations with friends and colleagues across the world,” said Rayner.

“I’m 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.”

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.

“I 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,” said Rowe.

“Research 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.”

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 ̽��ֱ�� 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

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

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

Self-confessed ‘nerd’ 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’s.

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

However, researchers at the ̽��ֱ�� 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 – a letter C might change to a letter T, for example. ‘Fingerprints’ left on our DNA can reveal what is responsible for this damage. As these mutations accumulate, they can have a profound effect on the function of cells and in some cases lead to tumours.

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

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

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

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

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

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

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

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

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

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

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

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

̽��ֱ��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 – sometimes more than we find in tumours

Serena Nik-Zainal

Alexas_Fotos

Sun

̽��ֱ��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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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

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Female scientists lead Cambridge success in Royal Society awards 2021

ta385 — Tue, 24 Aug 2021 12:00:00 +0000

Bell Burnell is one of twelve former and current Cambridge researchers, including six women, to be recognised in 2021 for their exceptional research and outstanding contributions to science.

Dame Jocelyn has been honoured for her work on the discovery of pulsars in the 1960s while she was a postgraduate student at New Hall (now Murray Edwards College) carrying out research at Cambridge's Cavendish Laboratory.

Past winners of the Copley Medal have included Charles Darwin, Albert Einstein and Dorothy Crowfoot Hodgkin. Dame Jocelyn said: “I am delighted to be the recipient of this year’s Copley Medal, a prize which has been awarded to so many incredible scientists.

“With many more women having successful careers in science, and gaining recognition for their transformational work, I hope there will be many more female Copley winners in the near future.

“My career has not fitted a conventional – male – pattern. Being the first person to identify pulsars would be the highlight of any career; but I have also swung sledgehammers and built radio telescopes; set up a successful group of my own studying binary stars; and was the first female president of the Institute of Physics and of the Royal Society of Edinburgh.

“I hope that my work and presence as a senior woman in science continues to encourage more women to pursue scientific careers”.

̽��ֱ��Copley Medal award includes a £25,000 gift which Dame Jocelyn will add to the Institute of Physics' Bell Burnell Graduate Scholarship Fund, which provides grants to graduate students from under-represented groups in physics.

Three female scientists currently working at Cambridge have been recognised in 2021. Professor Sadaf Farooqi from the MRC Metabolic Diseases Unit receives the Croonian Medal and Lecture, together with Sir Stephen O'Rahilly, for their seminal discoveries regarding the control of human body weight, resulting in novel diagnostics and therapies, which improve human health.

Dr Serena Nik-Zainal from the MRC Cancer Unit has been awarded the Francis Crick Medal and Lecture, for her contributions to understanding the aetiology of cancers by her analyses of mutation signatures in cancer genomes, which is now being applied to cancer therapy.

Professor Anne Ferguson-Smith from the Department of Genetics and currently the ̽��ֱ��’s Pro-Vice-Chancellor for Research receives the Buchanan Medal, for her pioneering work in epigenetics, her interdisciplinary work on genomic imprinting, the interplay between the genome and epigenome, and how genetic and environmental influences affect development and human diseases.

Former Cavendish Laboratory Research Fellow, Professor Michelle Simmons, has won the Bakerian Medal and Lecture, for her seminal contributions to our understanding of nature at the atomic-scale by creating a sequence of world-first quantum electronic devices in which individual atoms control device behaviour.

Professor Frances Kirwan, alumna and Honorary Fellow of Clare College, received the Sylvester Medal, for her research on quotients in algebraic geometry, including links with symplectic geometry and topology, which has had many applications.

Other current Cambridge researchers honoured include Dr Sjors Scheres from the MRC Laboratory of Molecular Biology. Scheres has been awarded the Leeuwenhoek Medal and Lecture for his ground-breaking contributions and innovations in image analysis and reconstruction methods in electron cryo-microscopy, enabling the structure determination of complex macromolecules of fundamental biological and medical importance to atomic resolution.

Emeritus Professor Michael Green from the Department of Applied Mathematics and Theoretical Physics has been awarded Royal Medal A for crucial and influential contributions to the development of string theory over a long period, including the discovery of anomaly cancellation.

̽��ֱ��Royal Society’s President, Sir Adrian Smith, said: “Through its medals and awards the Royal Society recognises those researchers and science communicators who have played a critical part in expanding our understanding of the world around us.”

“From advancing vaccine development to catching the first glimpses of distant pulsars, these discoveries shape our societies, answer fundamental questions and open new avenues for exploration.”

Find the full list of 2021 Royal Society medal, award and prize winners here.

Professor Dame Jocelyn Bell Burnell has become only the second woman to be awarded the Royal Society’s prestigious Copley Medal, the world’s oldest scientific prize.

I hope there will be many more female Copley winners in the near future

Jocelyn Bell Burnell

https://www.youtube.com/watch?v=z_3zNw91MSY

Professor Dame Jocelyn Bell Burnell

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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

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