̽��ֱ�� of Cambridge - Strangeways Research Laboratory

A landmark study of health and lifestyle celebrates its 20th birthday

amb206 — Wed, 09 Oct 2013 15:00:00 +0000

Participants in the EPIC-Norfolk Study will be meeting in Norwich tomorrow to celebrate a project that is making substantial contributions to our understanding of the role of lifestyle, in particular, diet and physical activity, and biological factors in health and disease.

̽��ֱ��research, which has helped us understand what we can do to maintain health in later life and has important implications for policy-makers, is sponsored by the ̽��ֱ�� of Cambridge. It is currently led by principal investigators Professor Kay-Tee Khaw and Professor Nick Wareham.

Continuing support from thousands of participants living in Norwich and the surrounding area is at the heart of the success of this study which relies on people giving up their time on a voluntary basis to contribute to the research.

Around 25,000 men and women living in Norfolk agreed to take part at the start of the study in 1993 and have been followed up to the present. Today the oldest participant is more than 90. All receive regular communications supplying them with updates on the research findings.

EPIC-Norfolk is part of one of the world’s biggest population studies with components in ten countries across Europe. When the programme was launched in the early 1990s, the people recruited were aged between 40 and 79.

̽��ֱ��research has led to a succession of papers which have added to knowledge about key aspects of health including common conditions such as heart disease and cancer, obesity, diabetes, eye health, and cognitive skills, and how these might be linked to lifestyle and genetic factors. Quality of life is an important strand of the research.

“We’re holding our Public Meeting event at St Andrews Hall, in Norwich as a way of thanking all the thousands of people who have helped us over the years – and will, we hope, continue to help us as we move into the next stage of the study,” said EPIC-Norfolk research co-ordinator, Shabina Hayat. “ ̽��ֱ��generosity of our participants is tremendous – their input makes the research possible.”

Though the original focus was on diet and cancer, from the outset of the study, the scope was widened to look at major causes of disability and loss of quality of life – including cardiovascular disease, osteoporosis and fractures, musculo-skeletal conditions such as arthritis, and more recently, memory loss, physical function, and eye diseases.

“Essentially data from the study represents a hugely valuable resource that can be used by our research partners and will eventually be used to inform future health policies and interventions to improve health,” said Ms Hayat.

̽��ֱ��EPIC-Norfolk study is unique in the detail with which it has examined diet, collecting data on 200 nutrients and more than 1,200 food groups. Food diaries were at the core of this strand of the work, enabling researchers to see patterns in food consumption. It was shown, for example, that just as alcohol consumption gets higher towards the end of the week and on Saturday, so does that of cakes and pies.

Key findings have included: the effects of ageing are highly variable with some older people having better physical and cognitive function than those 30 years younger; red and processed meat is associated with greater colorectal cancer risk, especially in individuals with low fibre consumption; and participants reporting higher television viewing (long periods of inactivity) have a particular risk of cardiovascular disease.

̽��ֱ��study has shown that people following four health behaviours (not smoking, being physically active, moderate alcohol intake and intake of five or more vegetables per day) can expect, on average, to live 14 years longer than those who don’t. Another finding is that it is better to eat a large breakfast and a small evening meal in terms of minimising weight gain.

̽��ֱ��current phase of the study is focusing on physical activity and body composition. When people put on weight, they collect fat in different areas of their body: some take on a pear shape and others an apple shape. Current research suggests that those with an apple shape (fat around the waist) have an increased risk of developing health-related problems such as diabetes.

By scanning participants to reveal distribution of fat around the body, EPIC-Norfolk aims to throw further light on this finding.

A landmark longitudinal study of health in the community will celebrate its 20th anniversary in Norwich tomorrow (10 October). ̽��ֱ��research, which adds significantly to our knowledge of public health, relies on volunteers who consistently give their time to science.

̽��ֱ��generosity of our participants is tremendous – their input makes the research possible.

Shabina Hayat

EPIC-Norfolk

A volunteer in the EPIC-Norfolk study

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Cancer: what's on the cards?

bjb42 — Mon, 04 Jan 2010 14:28:37 +0000

How likely we are to develop cancer is determined by our genes and our lifestyle. Likening this to a hand of cards, the risk of cancer depends on whether we inherit good cards or bad cards and also how we play them (our lifestyle). Some genes carry a very high risk, which is why some individuals have a particularly strong family history of cancer. Most of the time, however, cancer risk is determined by a combination of genes conferring a more moderate risk; nevertheless, the overall risk can be high (a bad hand) if there are enough of these genes.

At Strangeways Research Laboratory (SRL) in Cambridge, the research groups of Professor Doug Easton, Dr Paul Pharoah and Dr Alison Dunning, supported with over £9 million of funding from Cancer Research UK, are working out the role of normal human genetic variation in cancer risk – essentially, which hands of cards are worse than others.

̽��ֱ��SEARCH begins

Several high-risk gene defects, such as mutations in BRCA1 and BRCA2 in breast cancer, have been identified through family studies. Work in the 1990s at SRL by Professor Sir Bruce Ponder, who is now Director of the Cancer Research UK Cambridge Research Institute (CRI), and Professor Easton helped track down these two genes. However, among the general population, these defects are usually rare, and most cancers are the result of inheriting several more-common gene mutations. For breast cancer, these more-common gene defects account for as much as 80% of inherited risk, according to findings at SRL.

‘ ̽��ֱ��trouble is, the individual effects of common genetic variants are small and to get reliable evidence about specific variants you need to sample large numbers of people,’ explained Professor Easton, Director of the Cancer Research UK Genetic Epidemiology Group. Key to finding these mutations has been the assembly at SRL of one of the largest population studies of cancer ever conducted, along with the unique expertise that the team has gathered together in cancer epidemiology, biostatistics, large-scale genetic analysis and public health medicine.

This work was started in 1996 by Professor Ponder and Professor Nicholas Day, who recruited Dr Paul Pharoah as a Clinical Fellow to enrol patients with breast cancer. ̽��ֱ��enrolment was later extended to include patients with ovarian, colorectal or uterine cancer, as well as participants with no history of cancer. ̽��ֱ��project, now called SEARCH, was further extended five years ago to include bladder, brain, kidney, oesophageal and pancreatic cancers, as well as melanoma and non-Hodgkin’s lymphoma. ‘Our early investment in well-curated and very large study sets, with blood samples, pathology review and clinical data, has been absolutely crucial as it has provided the statistical power for reliable conclusions about common genetic variants,’ explained Professor Ponder. Today, SEARCH numbers nearly 27,000 cases and normal controls from the East Anglia region, providing a remarkable and growing resource: by 2013, the hope is that this will have expanded to 35,000.

Going global

‘SEARCH has shown that the size of the dataset is really important for assessing the impact of common genetic variants accurately,’ explained Dr Pharoah, who leads a research group at SRL from the Department of Oncology. ‘ ̽��ֱ��logical next step was to combine data from SEARCH with other studies that had been happening worldwide.’

Cambridge now coordinates five international consortia of study groups: two consortia studying breast cancer, one each studying ovarian and prostate cancers, and a newly formed consortium to examine genetic differences underlying adverse side-effects from cancer radiotherapy (see below). From SRL, the consortia pull in not just SEARCH but also other studies such as ProtecT, a prostate cancer study led by Cambridge’s Professor of Surgical Oncology, David Neal, together with Professor Freddie Hamdy in Oxford and Professor Jenny Donovan in Bristol; and the familial breast cancer study EMBRACE, led by Professor Easton. ̽��ֱ��scale of the endeavour is unprecedented in population studies, and the European Union has recently awarded €12 million to coordinate these large-scale genetic studies in breast, ovarian and prostate cancers.

‘Apart from increasing the reliability of the data,’ said Professor Easton, ‘the international consortia afford the opportunity to study populations from different parts of the world where different genetic and lifestyle factors are operating.’

Gene hunting

Improvements in technology that would have been hard to imagine when SEARCH began are now being used to analyse the data, demonstrating the enormous foresight in setting up such a resource a decade ago.

‘We know that there are about 10 million variants in the genome, but choosing the right ones to test for association with cancer has in the past owed a great deal to chance, with the result that very few positive associations were identified,’ said Dr Dunning, who leads the high-throughput laboratory team within the SRL. ‘Now, though, thanks both to the ability to carry out genome-wide scans and the samples collected through the international consortia, we can pinpoint the variants that are definitively linked to the risk of cancer.’

A full genome scan for breast cancer, the first of its kind, was completed in 2007 by the researchers and published in Nature. Full genome scans of prostate and ovarian cancers have since followed in Nature Genetics. In the latest scan, published in October 2009, the genomes of 38,000 men with and without prostate cancer were analysed for over 43,000 single differences in DNA (called single nucleotide polymorphisms or SNPs), revealing multiple new cancer gene regions.

To date, 13 predisposing gene regions have been identified for breast cancer, five for ovarian cancer and 27 for prostate cancer, findings that have significant implications for targeted screening and prevention in the future. Since most of these newly discovered regions contain genes that had not previously been considered in cancer, they will also provide new insights into the biology of the disease. Going forward, Professor Ponder’s group at the CRI is developing phenotypic assays as a read-out of cancer risk, studying how risk genes exert their function and searching for molecular markers for future studies of early diagnosis and prevention. Professor Fiona Watt at the Wellcome Trust Centre for Stem Cell Research is also studying the biological effects caused by these gene defects to understand what goes wrong in cancer.

Professor Neal, in the Department of Oncology and CRI, has been investigating whether a protein made by one of the newly discovered prostate loci can be used as a screening and diagnostic marker in prostate cancer since it can be measured in serum and urine. Early results suggest not only loss of the protein in prostate cancer, but also a decrease in men who possess the high- risk form of the gene but who have not yet developed prostate cancer.

Translational tools

But what does this all mean to understanding our own risk? For breast and ovarian cancer, Dr Antonis Antoniou and Professor Easton have developed a computer model named BOADICEA that can predict an individual’s risk of these cancers. ̽��ֱ��tool is already being used by genetic counsellors to identify high-risk individuals, referring them for counselling and regular screening if appropriate, and providing advice about ways to lower their risk. As new data come to light from the genome scans, BOADICEA will continually be improved, providing increasingly accurate information to individuals wishing to know the hand of genetic cards that they’ve been dealt.

BCAC: Breast Cancer Association Consortium

BOADICEA: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm

CIMBA: Consortium of Investigators of Modifiers of BRCA1/2

EMBRACE: Epidemiological Study of Familial Breast Cancer

OCAC: Ovarian Cancer Association Consortium

PRACTICAL: Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome

ProtecT: Prostate Testing for Cancer and Treatment

SEARCH: Studies of Epidemiology and Risk Factors in Cancer Heredity

For more information, please contact Professor Doug Easton (doug.easton@srl.cam.ac.uk), Dr Paul Pharoah (paul.pharoah@srl.cam.ac.uk) and Dr Alison Dunning (alisond@srl.cam.ac.uk) at the Strangeways Research Laboratory or visit the SEARCH website.

Scientists at Strangeways Research Laboratory are leading the search for the ‘genetic cards’ that determine an individual’s risk of cancer.

Ben Alford on Flickr

Cards

Worldwide consortia led by Strangeways Research Laboratory

BCAC: 100,000 breast cancer cases and controls; 55 study groups

CIMBA: 25,000 breast cancer cases and controls; 42 study groups

OCAC: 30,000 ovarian cancer cases and controls; 34 study groups

PRACTICAL: 25,000 prostate cancer cases and controls; 27 study groups

Radiogenomics Consortium: newly formed; 23 study groups

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