̽��ֱ�� of Cambridge - Centre for Cancer Genetic Epidemiology

AI can be good for our health and wellbeing

cjb250 — Mon, 07 Apr 2025 08:00:08 +0000

Cambridge researchers are looking at ways that AI can transform everything from drug discovery to Alzheimer's diagnoses to GP consultations.

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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Online tools transform outcomes for cancer patients

ta385 — Thu, 21 Oct 2021 06:00:00 +0000

PREDICT Breast and Prostate, powerful online risk communication tools developed by Cambridge researchers, have helped thousands of patients across the world reach better clinical outcomes, avoid unnecessary treatments and suffer less distress.

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

Globe

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Detailed genetic study provides most comprehensive map of risk to date of breast cancer risk

cjb250 — Tue, 07 Jan 2020 16:00:31 +0000

̽��ֱ��results, published today in the journal Nature Genetics, provide the most comprehensive map of breast cancer risk variants to date. ̽��ֱ��researchers involved, from over 450 departments and institutions worldwide, say the findings will help provide the most detailed picture yet of how differences in our DNA put some women at greater risk than others of developing the disease.

̽��ֱ��majority of the DNA is identical between individuals, but there are some differences, known as genetic variants, and these changes can have a profound effect, increasing an individual’s susceptibility to disease.

Our DNA – the blueprint for the human body – contains between 20,000-25,000 genes. Many of these code for proteins, the building blocks that make up the human body. Genetic variants can be located within genes, altering the protein. However, most of genetic variants are located outside genes, sometimes regulating the function of genes, turning their ‘volume’ up or down or even off. Finding which gene is targeted by these variants is not straightforward.

Most diseases are complex, polygenetic diseases – in other words, no single genetic variant or gene causes the disease, but rather the combination of a number of them act together to increase the likelihood that an individual will develop a particular disease. Breast cancer is one such disease.

Previous genome-wide association studies (GWAS), which involve comparing the DNA of patients against that of healthy controls, have found around 150 regions of the genome that clearly affect breast cancer risk. Within these regions, researchers know there are one or more genetic changes that affect the risk of developing cancer, but rarely are they able to pinpoint the specific variants or genes involved. Fine-mapping studies, such as this one, allow scientists to narrow down which variants contributing to the disease, how they might work and predict which are the genes involved.

“We know from previous studies that variants across our DNA contribute towards breast cancer risk, but only rarely have scientists have been able to identify exactly which genes are involved,” said Dr Laura Fachal from the Wellcome Sanger Institute. “We need this information as it gives us a better clue to what is driving the disease and hence how we might treat or even prevent it.”

In this new study, researchers from hundreds of institutions worldwide collaborated to compare the DNA of 110,000 breast cancer patients against that of some 90,000 healthy controls. By looking in much closer detail than was previously possibly, they identified 352 risk variants. It is not yet clear exactly how many genes these target, but the researchers have identified 191 genes with reasonable confidence; less than one in five of these had been previously recognised.

“This incredible haul of newly-discovered breast cancer genes provides us with many more genes to work on, most of which have not been studied before,” said Dr Alison Dunning from the ̽��ֱ�� of Cambridge. “It will help us build up a much more detailed picture of how breast cancer arises and develops. But the sheer number of genes now known to play a role emphasises how complex the disease is.”

Of the newly-discovered genetic variants, a third predispose women towards developing hormone-responsive breast cancer, the type of disease found in four out of five breast cancer patients, which respond to hormonal treatments such as tamoxifen. 15% of the genetic variants predispose women to the rarer type, estrogen-receptor-negative breast cancer. ̽��ֱ��remaining genetic variants play a role in both types of breast cancer.

In the majority of cases, the genetic change affected gene expression – in other words, how active a particular gene was and how much of a particular protein it created – rather than altering the type of protein itself. For instance, nine different variants regulate the same gene, the Estrogen Receptor (ESR1) gene. Many other variants affect places in the DNA where the Estrogen Receptor protein binds, and, in turn regulates other genes. This highlights the importance of the ESR1 gene and its protein product, the Estrogen Receptor, in breast cancer development.

While each genetic variant only increases the risk of developing breast cancer by a very small amount, the researchers say that added together, these will allow them to ‘fine tune’ genetic testing and give women a much clearer picture of their genetic risk. This will then allow doctors and clinicians to provide advice on the best strategy for reducing their risk and preventing onset of the disease.

Professor Doug Easton, also from the ̽��ֱ�� of Cambridge, said: “Our work would not have been possible without the help of the 200,000 volunteers who allowed us to study their DNA. It is also testament to the work of hundreds of researchers from all over the world who collaborated on this study.”

Reference
Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics; 7 Jan 2020; DOI: 10.1038/s41588-019-0537-1

A major international study of the genetics of breast cancer has identified more than 350 DNA ‘errors’ that increase an individual’s risk of developing the disease. ̽��ֱ��scientists involved say these errors may influence as many as 190 genes.

̽��ֱ��sheer number of genes now known to play a role emphasises how complex the disease is

Alison Dunning

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DNA

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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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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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