̽��ֱ�� of Cambridge - Douglas Easton

Back to BRCA: the discovery of a breast cancer risk gene

cjb250 — Mon, 07 Oct 2024 08:00:50 +0000

In 1994, a landmark paper identified a gene – BRCA1 – that significantly increases the risk of breast and ovarian cancers when faulty. Thirty years on, we look at the major impact it has had on how we understand and treat cancer – and why there is still much to learn.

International collaboration identifies new breast cancer susceptibility genes

Anonymous — Thu, 17 Aug 2023 15:00:18 +0000

̽��ֱ��study, published in Nature Genetics, was led by teams at the ̽��ֱ�� of Cambridge and Université Laval, Quebec.

Current genetic tests for breast cancer only consider a few genes, such as BRCA1, BRCA2, and PALB2. However, these only explain a minority of the genetic risk, suggesting that more genes remain to be identified.

Researchers looked at genetic changes in all genes in 26,000 women with breast cancer and 217,000 women without breast cancer. These included women from eight countries in Europe and Asia.

Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology at the ̽��ֱ�� of Cambridge, who co-led the study, said: "To our knowledge, this is the largest study of its kind. It was made possible through the use of data from multiple collaborators in many countries, as well as publicly available data from the UK Biobank.”

̽��ֱ��team found evidence for at least four new breast cancer risk genes, with suggestive evidence for many others. ̽��ֱ��team say identification of these new genes will contribute to our understanding of the genetic risk of breast cancer and help improve risk prediction by better identifying those women at higher risk of the disease.

̽��ֱ��findings will better inform approaches to breast screening, risk reduction and clinical management. ̽��ֱ��aim is to integrate this information into a comprehensive risk prediction tool currently used worldwide by health professionals.

"Improving genetic counselling for high-risk women will promote shared decision-making regarding risk reduction strategies, screening and determination of treatment options," said Professor Jacques Simard of Université Laval, co-lead of the study.

“Although most of the variants identified in these new genes are rare, the risks can be significant for women who carry them. For example, alterations in one of the new genes, MAP3K1, appear to give rise to a particularly high risk of breast cancer.”

Before this information can be used in a clinical setting, scientists need to validate the results in further datasets.

"We need additional data to determine more precisely the risks of cancer associated with variants in these genes, to study the characteristics of the tumours, and to understand how these genetic effects combine with other lifestyle factors affecting breast cancer risks," added Professor Easton.

̽��ֱ��discovery of these novel genes also provides crucial information on the biological mechanisms underlying cancer development, potentially opening the way to identifying new treatments.

̽��ֱ��study was funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation, the European Union Horizon programme, the Wellcome Trust and the International Alliance for Cancer Early Detection.

Reference
Wilcox, N et al. Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk. Nat Gen; 17 Aug 2023; DOI :10.1038/s41588-023-01466-z

Adapted from a press release by Université Laval

A large-scale international collaboration has identified new genes associated with breast cancer that could eventually be included in tests to identify women at increased risk of the disease.

To our knowledge, this is the largest study of its kind

Douglas Easton

Anna Tarazevich

Two women holding pink ribbons

̽��ֱ��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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Nine Cambridge scientists among the new 2022 Fellows announced by the Royal Society

jg533 — Tue, 10 May 2022 11:33:12 +0000

̽��ֱ��Royal Society is a self-governing Fellowship made up of the most eminent scientists, engineers and technologists from the UK and the Commonwealth. Its Foreign Members are drawn from the rest of the world.

̽��ֱ��Society’s fundamental purpose is to recognise, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity.

This year, a total of 51 Fellows, 10 Foreign Members, and one Honorary Fellow have been selected for their outstanding contributions to science.

Sir Adrian Smith, President of the Royal Society said: “It is an honour to welcome so many outstanding researchers from around the world into the Fellowship of the Royal Society.

“Through their careers so far, these researchers have helped further our understanding of human disease, biodiversity loss and the origins of the universe. I am also pleased to see so many new Fellows working in areas likely to have a transformative impact on our society over this century, from new materials and energy technologies to synthetic biology and artificial intelligence. I look forward to seeing what great things they will achieve in the years ahead.”

̽��ֱ��Cambridge Fellows are:

Professor Graham Burton FMedSci FRS

Mary Marshall and Arthur Walton Professor Emeritus of the Physiology of Reproduction, ̽��ֱ�� of Cambridge

Burton is a reproductive biologist whose research has focused on the early stages of human pregnancy. In particular, he showed how the placenta is established in a protective low-oxygen environment, stimulating its own development through interactions with the uterus. He demonstrated that aberrations in the early stages of placental development can adversely affect the life-long health of mother and offspring. Burton was founding Director of the Centre for Trophoblast Research, and founding Chair of the Strategic Research Initiative Cambridge Reproduction.

He said: “I am delighted to receive this recognition for myself and the field of reproductive biology, and thank colleagues and collaborators for their contributions over the years.”

Professor Roberto Cipolla FREng FRS

Professor of Information Engineering, Department of Engineering, ̽��ֱ�� of Cambridge

Cipolla is distinguished for his research in computer vision and his contributions to the reconstruction, registration and recognition of three-dimensional objects from images. These include novel algorithms for the recovery of accurate 3D shape, visual localisation and semantic segmentation and their translation into commercial products.

He said: "This is the ultimate honour for any scientist and recognises the amazing contribution of my students, collaborators and mentors in my 30 years at Cambridge. I am also very fortunate to be working in the field of computer vision and machine learning at a time of revolutionary progress and ground-breaking applications.”

Professor Douglas Easton FMedSci FRS

Professor of Genetic Epidemiology, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, ̽��ֱ�� of Cambridge

Easton’s main research interests are in cancer genetics. He analyses large population studies to identify genetic variants that predispose to cancer, and to understand how they combine together with other factors to determine cancer risk. His work has characterised many important cancer genes such as BRCA1 and BRCA2, and identified of hundreds of common cancer predisposition variants in the non-coding genome. He co-developed the BOADICEA risk prediction model now used worldwide to guide genetic counselling and cancer prevention.

He said: "I am truly delighted and honoured to be elected to the Fellowship of the Royal Society. This prestigious honour is a tribute the work of many wonderful colleagues in Cambridge and worldwide, over many years, who have made the research possible."

Professor Robin Franklin FMedSci FRS

Formerly Professor of Stem Cell Medicine, Wellcome - MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge; now Principal Investigator, Altos Labs - Cambridge Institute

̽��ֱ��central question of Franklin’s career is 'how do tissues regenerate?' To address this question, he has studied the brain, an organ notorious for its poor regenerative capacity. Working with many excellent colleagues, he has described how stem cells in the adult brain regenerate oligodendrocytes - the cells responsible for making the insulating myelin sheath around nerve fibres - once they are lost in diseases such as multiple sclerosis (MS); how this process declines with age; and it can be reversed. ̽��ֱ��work has led to two regenerative medicine trials in MS.

He said: “I am absolutely delighted to have been elected a Fellow of the Royal Society - it is a huge honour.”

Professor Richard Gilbertson FMedSci FRS

Li Ka Shing Chair of Oncology and Head of Department of Oncology, ̽��ֱ�� of Cambridge, Director of Cancer Research UK Cambridge Centre and Senior Group Leader, Cancer Research UK Cambridge Institute

Gilbertson, a paediatric physician-scientist, has identified the origins of common and aggressive childhood brain tumours and many of the genetic alterations that drive these tumours. His research has helped establish a direct link between disordered development and the multiple different brain tumour types observed in children: contributing directly to their classification by the World Health Organisation (WHO); changing the way conventional treatments are used, sparing children from unnecessary side effects; and underpinning clinical trials of new therapies.

Gilbertson said: “I am truly delighted and humbled to receive this recognition that I share with all the wonderful students, trainees and colleagues I have worked with over the years.”

Professor Paul Lehner FMedSci FRS

Professor of Immunology and Medicine, Cambridge Institute for Medical Research, ̽��ֱ�� of Cambridge

Lehner studies virus-host antagonism and how our genome is defended from invasion by RNA-derived retroelements such as HIV. His discovery of the ‘HUSH’ epigenetic silencing complex explains how the genome distinguishes new genetic material from endogenous genes through recognition of intronless DNA. This work uncovered an unanticipated surveillance system that discriminates ‘self’ from ‘non-self’ genomic DNA and defends our genome against the reverse flow of genetic information (RNA to DNA), paving the way to novel applications in medicine and biotechnology.

Lehner said: “I’m absolutely delighted to be elected to the Fellowship of the Royal Society; I’ve been fortunate to work with incredibly talented people and this honour recognises the commitment of the many past and present members of my group who have contributed to our work.”

Professor Roberto Maiolino FRS

Director of the Kavli Institute for Cosmology and Professor of Experimental Astrophysics, ̽��ֱ�� of Cambridge

Maiolino studies the formation of galaxies using observations collected at some of the largest ground-based and space telescopes. He has obtained key results on the interplay between the evolution of galaxies and the supermassive black holes at their centres. He has also investigated the enrichment of chemical elements across the cosmic epochs, as well as the origin and nature of dust particles in the early Universe.

He said: “I am truly honoured by such a prestigious appointment. Being a Fellow of the Royal Society will certainly foster my research activities and will allow me to further promote exciting, cutting-edge projects.”

Professor Angelos Michaelides FRS

1968 Professor of Chemistry, Yusuf Hamied Department of Chemistry, ̽��ֱ�� of Cambridge

Michaelides’ work involves the development and application of theoretical methods to better understand contemporary problems in chemistry, physics, and materials science. His group places a particular focus on developing and applying computer simulation approaches that provide the fundamental molecular-level insight needed to help address contemporary global challenges related to water, energy, and the environment.

He said: “Holy moly! I’m delighted to have been elected an FRS and very grateful to all the outstanding students, post-docs, collaborators, and mentors I’ve had over the years without whom this would never have happened.”

Professor Jason William Chin FMedSci FRS

Head, Centre for Chemical and Synthetic Biology, and Joint Head, Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology; Professor of Chemistry and Chemical Biology, Yusuf Hamied Department of Chemistry, ̽��ֱ�� of Cambridge; Associate Faculty in Synthetic Genomics, Wellcome Sanger Institute

Chin has engineered the genetic code of living cells to synthesise modified proteins and non-canonical polymers. To accomplish this, he created new translational machinery and codons to reprogram the genetic code, going well-beyond prior work using amber suppression. He then completely synthesised a bacterial genome in which he reduced the number of sense codons in its genetic code. ̽��ֱ��codons thus unused were reassigned to encode non-canonical amino acids. Chin's fundamental advances have been widely used to drive discovery, including to define the molecular consequences of post-translational modifications, define protein interactions in cells, and provide mechanistic insight into enzymes.

̽��ֱ��nine Cambridge researchers were all selected for their exceptional contributions to science.

It is an honour to welcome so many outstanding researchers from around the world into the Fellowship of the Royal Society.

Sir Adrian Smith, President of the Royal Society

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Genetic tool can identify Asian women at higher risk of breast cancer

Anonymous — Fri, 31 Jul 2020 09:00:00 +0000

̽��ֱ��tool, called a Polygenic Risk Score (PRS), separates people into different risk groups based on their genetic sequence to predict their future risk of developing breast cancer. ̽��ֱ��results can empower women to decide which screening and prevention is right for them, and help reduce inefficiency, unnecessary cost, and even possible harm caused by over-diagnosis.

This is the first large study of the PRS in an Asian population. Previously, Asian studies were nearly six times smaller than studies in European women, and due to lack of data in Asians it was unclear if PRSs are effective in predicting breast cancer risk in non-European women.

“We have been developing a model for predicting breast cancer risk in European women that includes the PRS and this is now approved for clinical use. This study is the first big step towards enabling the use of such tools in the clinical management of women of Asian ancestry,” said Professor Antonis Antoniou at the ̽��ֱ�� of Cambridge’s Department of Public Health and Primary Care, and co-lead of the study.

Through the significant increase in data from Malaysia and Singapore, PRSs have been shown to help identify more accurately who is at high risk of breast cancer. ̽��ֱ��results suggest that only 30% of Malaysian and Singaporean women have a predicted risk similar to that of European women, and that using the PRS accurately identifies these high-risk women. ̽��ֱ��study is published today in the journal Nature Communications.

“Combining genetic factors into one comprehensive model is critical to move from the research to a tool for women to use. We evaluated the PRS in 45,212 Asian women, from Singapore, Malaysia, Japan, Korea, China, Hong Kong, Thailand, Taiwan, USA, and Canada. Studies such as these require large sample sizes, and so, bringing together patients from ̽��ֱ�� Malaya, Subang Jaya Medical Centre, National ̽��ֱ�� Hospital, Singapore, and six other major treatment centres in Singapore really gave us the sample size to be able to evaluate the tool in Asians,” said Associate Professor Ho Weang Kee at the ̽��ֱ�� of Nottingham in Malaysia, and first author of the study.

Women are generally recommended to start screening at age 50. However, in most Asian countries, many women who could be at risk of breast cancer do not go for screening. This leads to late detection and a lower survival rate.

“Our study is a critical piece of the puzzle that helps us better understand breast cancer risks in different women around the world. There are differences in the genetic make-up of Asian women compared to women of European descent, which means their propensity to develop breast cancer may be different. Understanding this can help us to work out why some women are at higher risk of the disease, which in turn should help us to improve screening, prevention and ultimately treatment of the disease,” said Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology at the ̽��ֱ�� of Cambridge, and co-lead of the study.

There is an urgent need to develop an appropriate screening strategy for Asian women. Malaysia anticipates a 49% increase in breast cancer cases from 2012 to 2025. Malaysia has a much lower five-year survival rate compared to other Asian countries at only 63%, whereas South Korea is at 92% and Singapore is at 80%.

“Risk-based screening may be particularly important in low- and middle-resource countries that do not have population-based screening, such as Malaysia. Without the funding for population-based screening, identifying individuals with higher risk may be an important strategy for early detection,” said Professor Nur Aishah Mohd Taib, Universiti Malaya Cancer Research Institute, Malaysia.

̽��ֱ��study involved a collaboration between Cancer Research Malaysia, the ̽��ֱ�� of Nottingham, the ̽��ֱ�� of Cambridge, the Universiti Malaya, Subang Jaya Medical Centre, National ̽��ֱ�� Health System, Genome Institute of Singapore, six hospitals in Singapore, and a large population-based prospective cohort from Singapore.

̽��ֱ��work was funded by the Medical Research Council and Academy of Sciences Malaysia via the Newton-Ungku Omar Fund, the Wellcome Trust Collaborative Science Award, Yayasan Sime Darby, Yayasan PETRONAS, and Estee Lauder Group of Companies.

Adapted from a press release by Cancer Research Malaysia.

A genetic study in Asian women, led by Malaysian scientists in collaboration with Singapore and the ̽��ֱ�� of Cambridge, has revealed that a genetic tool developed to help assess breast cancer risk in European women also works in Asian women. This could help address the rising incidence of breast cancer in Asia.

This study is the first big step towards enabling the use of such tools in the clinical management of women of Asian ancestry

Antonis Antoniou

Sam Albury on Unsplash

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Major study of genetics of breast cancer provides clues to mechanisms behind the disease

cjb250 — Mon, 23 Oct 2017 15:39:07 +0000

Of these variants, reported today in the journals Nature and Nature Genetics, 65 are common variants that predispose to breast cancer and a further seven predispose specifically to oestrogen-receptor negative breast cancer – the subset of cases that do not respond to hormonal therapies, such as the drug tamoxifen.

Breast cancer is caused by complex interactions between a large number of genetic variants and our environment. ̽��ֱ��inherited component of breast cancer risk is due to a combination of rare variants in genes such as BRCA1 and BRCA2 that confer a high risk of the disease, and many commoner genetic variants that each confer only a small risk. ̽��ֱ��newly identified risk regions nearly double the number that are already known, thereby bringing the number of known common variants associated with breast cancer to around 180.

̽��ֱ��findings are the result of work by the OncoArray Consortium, a huge endeavour involving 550 researchers from around 300 different institutions in six continents. In total, they analysed genetic data from 275,000 women, of whom 146,000 had been diagnosed with breast cancer.

Professor Doug Easton from the Centre for Cancer Genetic Epidemiology and a Fellow at Homerton College, the ̽��ֱ�� of Cambridge, one of the lead investigators on the study, says: “These findings add significantly to our understanding of the inherited basis of breast cancer. As well as identifying new genetic variants, we have also confirmed many that we had previously suspected. There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved.”

By combining epidemiological data with other data from breast tissue, the researchers were able to make plausible predictions of the target genes in the large majority of cases. In addition, they showed for the first time that these genes are often the same as those that are altered in breast tumours – when a tumour develops, the DNA within the cancer cells themselves mutates.

Most of the variants found by OncoArray were not found within genes, but rather within regions of the genome that regulate the activity of nearby genes. When the researchers looked at the pattern of these genetic regions, they discovered that this differed from that of those regions involved in predisposition to other common diseases.

Professor Peter Kraft at Harvard TH Chan School of Public Health, USA, says: “Given the size of these studies, we expected that we would find a lot of new breast cancer risk variants, but the studies tells us a lot more about which genes are involved, revealing many previously unsuspected genes and genetic mechanisms underlying breast carcinogenesis. This should provide guidance for a lot of future research.”

Around 70% of all cases of breast cancer are oestrogen-receptor positive, meaning that the cancer cells have a particular protein (known as a receptor) that responds to the female sex hormone oestrogen, enabling the tumour to grow. However, not all cancer cells carry this receptor – these are known as oestrogen-receptor negative. ̽��ֱ��studies identified genetic regions specifically associated with either oestrogen-receptor positive or oestrogen receptor negative breast cancer, underscoring the fact that these are biologically distinct cancers that develop differently.

“These findings may inform improved risk prediction, both for the general population and BRCA1 mutation carriers,” says Associate Professor Roger Milne at Cancer Council Victoria in Melbourne. “A better understanding of the biological basis of oestrogen receptor negative breast cancer may lead to more effective preventive interventions and treatments.”

̽��ֱ��risk variants identified in the two studies are common: while some are carried by one woman in a hundred, others are carried by more half of all women. Individually, the risks conferred by each variant are modest; however, because they are common and their effects multiply together, the combined effect is considerable. For example, the researchers estimated that one percent of women have a risk of breast cancer that is more than 3 times greater than the population at large. Larger differences in risk can be found if the genetic variants are combined with other hormonal and lifestyle factors that influence breast cancer risk.

̽��ֱ��researchers believe these differences may be sufficient to change practice, such as in how women at different risks are screened. In many countries, women are offered screening by mammography from age 50; women at increased risk because of a family history can be offered screening earlier, and those at particularly high risk can be offered screening by MRI, which is more sensitive.

“Using data from genomic studies, combined with information on other known risk factors, will allow better breast cancer risk assessment, therefore helping to identify a small but meaningful proportion of women at high risk of breast cancer,” says Professor Jacques Simard at Université Laval, Quebec city, Canada.

“These women may benefit from more intensive screening, starting at a younger age, or using more sensitive screening techniques, allowing early detection and prevention of the disease. At the same time, this personalised information will also be useful to adapt screening modalities for women at substantially lower risk.”

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “This study is a great example of how international collaboration can help improve the understanding of cancer. ̽��ֱ��results, gathered from around the world, help pinpoint the genetic changes linked to a women’s risk of breast cancer. Learning which women are at higher risk of breast cancer could help identify who may benefit from earlier screening, and spare women at a lower risk from having to attend screening if it’s unlikely to benefit them.”

Reference
Michailidou, K et al. Association analysis identifies 65 new breast cancer risk loci. Nature; 23 Oct 2017; DOI: 10.1038/nature24284

Milne, RL et al. Identification of ten variants associated with risk of estrogen receptor negative breast cancer. Nature Genetics; 23 Oct 2017; DOI: 10.1038/ng.3785

Funding
Genotyping of the OncoArray was principally funded from three sources: the Personalised Risk Stratification for Early Detection and Prevention of Breast Cancer (PERSPECTIVE) project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec, and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project; and Cancer Research UK. BCAC is funded by Cancer Research UK and the European Union Horizon 2020 programme (BRIDGES and B-CAST).

Seventy-two new genetic variants that contribute to the risk of developing breast cancer have been identified by a major international collaboration involving hundreds of researchers worldwide.

There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved

Doug Easton

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Family history and location of genetic fault affect risk for carriers of key breast and ovarian cancer genes

cjb250 — Tue, 20 Jun 2017 15:00:31 +0000

Cancer is caused by a combination of inherited genetic faults and environmental factors. While many hundreds of genetic mutations each increase an individual’s risk by a small amount, faults in two particular genes – BRCA1 and BRCA2 – are known to greatly elevate the risk of breast and ovarian cancers.

̽��ֱ��clinical management of women with faults in the BRCA1 and BRCA2 genes requires accurate estimates of their risk of developing breast cancer and how this changes with age. These can be used to estimate how prevention strategies such as medication, surgery and changing lifestyle factors reduce a woman’s risk, and can assist with decisions about the age to commence cancer screening, hence enabling better-informed decision-making.

Almost all previous reports on cancer risks for BRCA1 and BRCA2 mutation carriers have been based on ‘retrospective’ studies – looking at women who had already developed cancer – and estimates are therefore susceptible to biases associated with such study designs, for example inaccuracies in family history reporting and assessment in women born many decades previously (when breast cancer incidence was much lower) that are not relevant to today’s women.

Prospective cohort studies, in which scientists recruit and follow over time carriers of the mutations who have not yet developed breast cancer, overcome these issues. But the prospective studies of women with the BRCA1 and BRCA2 genes published to date have been very small, with the largest based on just 64 incident breast cancers.

Now, in a study published in JAMA: ̽��ֱ��Journal of the American Medical Association, an international team of researchers led by the ̽��ֱ�� of Cambridge, UK, has recruited almost 10,000 mutation carriers for a prospective cohort study. This enabled the team to estimate more precisely the breast and ovarian cancer risks for women with faults in BRCA1 and BRCA2.

“We have been able to provide the most precise estimates of age-specific risks to date,” says the study’s lead author, Dr Antonis Antoniou from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge. “These should provide more confidence in the counselling and clinical management of women with faults in the BRCA1 and BRCA2 genes.”

̽��ֱ��researchers found that 72% of women carrying a faulty BRCA1 gene will develop breast cancer risk and 44% will develop ovarian cancer by age 80. Similarly, they found that 69% of women carrying a faulty BRCA2 gene will develop breast cancer and 17% will develop ovarian cancer by age 80. However, for both cancers, a woman’s family history affected the risk – in other words, if a woman’s relative had had a breast cancer diagnosis, then her own risk would be higher than that of a carrier with no family history.

̽��ֱ��researchers also found that the position of the specific fault within the gene affected the cancer risk. Mutations in genes occur when the ‘letters’ of DNA – A, C, G and T – get ‘mistyped’ and replaced with a different letter.

“ ̽��ֱ��results show clearly and for the first time in a prospective study, that the cancer risks for women with faults in BRCA1 and BRCA2 depend both on the precise mutation and the woman’s family cancer history,” says Professor Douglas Easton, also from Cambridge and principal investigator of the UK-based EMBRACE study, the largest national cohort of women with mutations that contributed to the study.

Advances in sequencing technologies have opened up the potential of screening all women for BRCA1 and BRCA2 mutations, rather than just those with a significant family history of cancer, as is currently the case in the UK and most other countries. Such population-based screening, however, depends on having reliable estimates of risk to provide to women with and without a family history.

“Now that we understand more clearly the risks faced by women who carry these genetic faults, we should be in a better position to counsel them about the outcomes from screening and prevention programmes,” says Professor Gareth Evans, Consultant in Medical Genetics and co-author from ̽��ֱ�� of Manchester.

“This will also have practical implications on clinical management decisions, for example on the timing of surgery in order to reduce cancer risk. Such decisions tend to be taken around childbearing age, but some women with lower risks may opt to delay surgery until they complete their families.”

̽��ֱ��cancer risk estimates obtained by the present study were made possible because of over two decades of investment from Cancer Research UK, the European Union and other funders in establishing and following the cohorts.

Professor Arnie Purushotham, Cancer Research UK’s senior clinical adviser, said: “Women who carry faulty BRCA genes are much more likely to develop breast or ovarian cancers, and this large study could help women and their doctors better understand their risk of developing these cancers.

“This information – combining family medical history and the specific position of the faults in the BRCA genes – could help women decide the steps that they may want to take to reduce their risk of breast cancer, such as preventative surgery, medication or lifestyle changes.”

Reference
Kuchenbaecker, KB et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA; 20 June 2017; DOI: 10.1001/jama.2017.7112

A large scale study of women carrying faults in important cancer genes should enable doctors to provide better advice and counselling for treatments and lifestyle changes aimed at reducing this risk.

̽��ֱ��results show clearly... that the cancer risks for women with faults in BRCA1 and BRCA2 depend both on the precise mutation and the woman’s family cancer history

Doug Easton

MIKI Yoshihito

DNA

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Breast cancer genetic variants found to alter how cells respond to oestrogen

cjb250 — Mon, 29 Feb 2016 16:52:02 +0000

Breast cancer is the most common type of cancer among women. Around one in eight women in the general population is expected to develop the disease at some point in her life. ̽��ֱ��majority of cases occur in women aged 50 and over.

̽��ֱ��female sex hormone oestrogen acts as a trigger, binding to a molecule known as an oestrogen receptor in most breast cells and triggering a cascade of signals that cause the cell to behave normally. However, the oestrogen receptor is switched off in some cells and these do not respond to the hormone.

An international collaboration, led by researchers at the ̽��ֱ�� of Cambridge and the QIMR Berghofer Medical Research Institute, examined the DNA surrounding the gene for the oestrogen receptor – known as ESR1 – in women with different types of breast cancer against those of healthy controls to identify genetic variants responsible for an increased risk of breast cancer. ̽��ֱ��results are published today in the journal Nature Genetics.

Among their findings, the researchers discovered five cancer-risk variants based within or around the ESR1 gene. This gene has long been known to be related to the risk and progress of breast cancer, but little is understood of how it works and why it should affect breast cancer.

Of the five variants discovered by the team, four were more strongly associated with tumours where the ESR1 gene is switched off, so the tumour cells have no oestrogen receptors. These represent around one fifth of breast cancers.

One of these four variants was of particular interest as it was associated with a rarer type of breast tumour that contain active receptors for the protein known as ‘human epidermal growth factor 2’ (HER2). Such tumours can be treated by the drug trastuzumab (marketed as Herceptin). This is believed to be the first time a specific genetic risk factor for HER2 positive breast tumours has been found.

Dr Stacey Edwards’ team from QIMR Berghofer, Brisbane, had been searching for gene regulatory elements around the ESR1 gene, which act like the volume controls on a radio or TV, turning the activity of the nearby genes up or down. There are two major types of gene regulators: ‘enhancers’, which increase activity of the genes express such that they make more protein, and ‘silencers’, which have the opposite effect.

When the Cambridge and Brisbane teams compared notes, they spotted that four of the breast cancer risk variants coincided with ‘volume-up’ enhancers. These particular regulators did not just affect the ESR1 gene but also other nearby genes. ̽��ֱ��variants that increased risk of breast cancer directly reduced the effectiveness of each enhancer, hence turning down the volume of ESR1 and the other nearby genes. This reduced the amount of oestrogen receptor produced by breast cells.

̽��ֱ��researchers say that their results suggest the ESR1 gene works with other nearby genes to affect breast cancer development.

̽��ֱ��fifth genetic variant was found to be more strongly associated with tumours where the oestrogen receptor is switched on. This variant coincides with and alters the effectiveness of ‘volume-down’ silencer, which means that it increases the amount of oestrogen receptor protein produced by breast cells.

“It’s interesting that all five of the genetic variants that we have found affect levels of oestrogen receptors in breast cells,” says Dr Alison Dunning from the Department of Oncology at the ̽��ֱ�� of Cambridge, one of the lead authors on the study. “This suggests that there may be a ‘Goldilocks’ level of these receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous.”

“As our research looks at how tumours with and without the oestrogen receptor are regulated, it’s possible it could help make sense of the enduring mystery of how tamoxifen works and why tumours develop in these two divergent ways,” says Dr Edwards, one of the study’s senior authors. “Our findings could open the way to developing new, more specific breast cancer preventions.”

̽��ֱ��genetic variants are all very common, each one carried by around one in three women. Each variant only increases the risk of developing breast cancer by a small amount.

Professor Doug Easton, another senior author from the ̽��ֱ�� of Cambridge, adds: “breast cancer is a very complex disease, with many genes, and other factors, contributing to an overall increased risk of developing the disease. These five common variants that we have identified will contribute to an eventual predictive test for breast cancer risk, and for determining the risk of the particular subtype of breast cancer, that will include hundreds of similar variants.”

Funding for the study came from organisations including the European Union, Cancer Research UK, the National Health and Medical Research Council of Australia and the Australian National Breast Cancer Foundation.

Dr Alan Worsley, Cancer Research UK’s senior science information officer, said: “We know that hundreds of genes are likely to play a role in how cancers start. And this latest study adds more detail to our genetic map of breast cancer risk, potentially helping understand which type of breast cancer is likely to develop based on a woman’s genetic makeup. Understanding more about each individual’s risk of cancer could help us find ways to potentially prevent the disease or pick it up in its earliest stages."

Reference
Dunning, AM et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1. RMND1 and CCDC170. Nature Genetics; published online 29 Feb 2016. DOI: 10.1038/ng.3521.

An international study of almost 120,000 women has newly identified five genetic variants affecting risk of breast cancer, all of which are believed to influence how breast cells respond to the female sex hormone oestrogen.

There may be a ‘Goldilocks’ level of oestrogen receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous

Alison Dunning

williami5

Breast cancer reflection

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Genetic screening could improve breast cancer prevention

cjb250 — Wed, 08 Apr 2015 23:00:00 +0000

Improving the accuracy of risk analysis using genetic screening could guide breast cancer prevention in several ways – for instance by offering high-risk women increased monitoring, personalised advice and preventative therapies.

̽��ֱ��research, a collaboration of hundreds of research institutions led by the ̽��ֱ�� of Cambridge and the Institute of Cancer Research, London, showed that a test for differences in 77 separate letters of DNA code could indicate a woman’s risk of developing breast cancer.

̽��ֱ��study, the most definitive of its type conducted so far, was funded by a range of organisations including Cancer Research UK and Breakthrough Breast Cancer, and is published today in the Journal of the National Cancer Institute.

̽��ֱ��researchers came up with a ‘score’ for each woman based on the letters they had in each of the 77 positions of their DNA code, using one of the world’s biggest databases of genetic information – called the Collaborative Oncological Gene-Environment Study (COGS).

They found a significant link between the score – called a ‘polygenic risk score’ – and a woman’s breast cancer risk. For example, a woman in the top 20 per cent for polygenic risk score was 1.8 times more likely to develop breast cancer than the average woman.

A woman in the top one per cent for the polygenic risk score was more than three times more likely to develop breast cancer than average – corresponding to a risk for these women of around one in three.
̽��ֱ��researchers also delved into a range of other elements of each woman’s cancer – such as its type, and the age it was diagnosed. ̽��ֱ��genetic score was particularly good at predicting risk in women who developed oestrogen receptor positive disease, the type of disease most responsive to hormonal treatments such as tamoxifen.

Analysing this panel of 77 genetic markers – all of which had previously been linked with slight increases in breast cancer risk on their own – was much more accurate in defining risk than previous tests that used fewer markers.

Importantly, the study also suggests that using this genetic testing alongside current measures would make current risk screening methods more accurate. For example, the researchers showed that the risk score could predict breast cancer risk both in women with and without a family history of the disease.

Lifetime risk of breast cancer for women with a history of breast cancer in their close family was 24.4 per cent if they were in the highest-scoring fifth – compared with 8.6 per cent if they were in the lowest fifth.
But for women without a history of breast cancer in their close family, the risks were 16.6 and 5.2 per cent respectively.

Study co-leader Professor Montserrat Garcia-Closas, Professor of Epidemiology at the Institute of Cancer Research, London, said: “Our study is the most definitive so far to show the clear benefits of using genetic testing for a large number of genetic risk factors in identifying women at elevated risk of developing breast cancer. This type of testing could fit alongside other standard risk measures, such as family history and body mass index, to improve our ability to target the best preventive treatments and advice to those women most likely to benefit from them."

̽��ֱ��researchers say it is important to work out how this type of test could be used widely in a healthcare, rather than in a research setting. Currently available tests can analyse a handful of high-risk genes, but outside of looking for changes to these genes in women with a history of breast cancer in their close family, genetic testing is not widely offered to women.

Study co-leader Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology at the ̽��ֱ�� of Cambridge, said: “Breast cancer genes are rarely out of the news, but we’ve now reached a crucial stage at which all this research can be combined to help target screening and advice to those women who need them the most.

“There’s still work to be done to determine how tests like this could complement other risk factors, such as age, lifestyle and family history, but it’s a major step in the right direction that will hopefully see genetic risk prediction become part of routine breast screening in the years to come.”

Nell Barrie, Senior Science Communications Manager at Cancer Research UK, said: “This study shows how the genetic map of breast cancer that scientists have been building up over the years might be used to identify women most at risk, so we can take steps to reduce their chances of developing the disease or catch it at the earliest possible stage.”

Dr Matthew Lam, Senior Research Officer at Breakthrough Breast Cancer, said: “In recent years we’ve learnt so much about genetic risk factors of breast cancer – in fact Breakthrough researchers had a hand in discovering over 60 of the genetic markers associated with the disease. What’s great to see now is that these findings are starting to be translated into practical methods to predict risk on an individual basis.”

Adapted from a press release from the Institute of Cancer Research.

A test for a wide range of genetic risk factors could improve doctors’ ability to work out which women are at increased risk of developing breast cancer, a major study of more than 65,000 women has shown.

Breast cancer genes are rarely out of the news, but we’ve now reached a crucial stage at which all this research can be combined to help target screening and advice to those women who need them the most.

Doug Easton

Dr Steven Harmes. Baylor ̽��ֱ�� Medical Center, Dallas Texas

Color-enhancement show magnetic resonance image (MRI) of individual breast

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