For hundreds of years the Scottish Highlands have resounded to the names of their famous clans: MacDonald, Campbell, Fraser, and many more. Each clan is a complex, branching family tree, starting from a single person but evolving over the years into a plethora of related but distinct groups.
Trying to untangle the different branches of a clan is a complicated and painstaking job for genealogists, poring over detailed histories and dusty parish records. But the family trees they construct from this information reveal the story of a clan’s evolution over time.
Now Charles Swanton and his team at the Francis Crick Institute, funded by Cancer Research UK, have carried out a similar painstaking analysis of data from more than 2,500 cancers, covering nine different tumour types.
Their study, published in the journal Science Translational Medicine, reveals the genetic relationships between different groups of cancer cells within an individual tumour, shedding light on the evolutionary processes at work as cancer grows and spreads within the body and how we might harness them to treat the disease more effectively in future.
A Freedom of Information (FOI) request by leading charity Bowel Cancer UK has highlighted a wide variation in tests for Lynch syndrome in bowel cancer patients under 50. Lynch syndrome is an inherited condition which can mean a higher risk of developing bowel cancer. Testing for Lynch syndrome will help identify family members who may have the condition and be at risk of bowel cancer. It can also affect treatment options. Lynch syndrome testing has been shown to be cost effective for the NHS, and is a required reflex test mandated by the Royal College of Pathologists and recommended by the British Society of Gastroenterologists.
Despite this testing is patchy. Just half of the hospital trusts in England that responded to the FOI request said they conduct tests among bowel cancer patients under 50 for Lynch syndrome, 10 of the trusts saying they had no plans to do so.
It’s not just England hospital trusts that are falling short. More than half of health boards in Wales do not screen patients under 50 with bowel cancer. In Scotland fifty per cent of health boards currently do not follow the guidelines for Lynch syndrome testing set in July last year by the Royal College of Pathologists. It’s a brighter picture in Northern Ireland where all health and social care trusts responded to say that they perform the test to identify possible Lynch syndrome patients.
The approach to testing is also widely varied among those hospitals which do screening for bowel cancer patients under 50. Testing is part of the core dataset for pathologists and should therefore be carried out automatically (known as reflex testing) for this group of young patients. However many trusts/health boards do not yet carry out this “reflex testing,” as stipulated in the Royal College of Pathologists’ guidelines. Scotland is in the process of developing a nationwide approach to testing. We believe a nationwide approach would provide the consistency needed to ensure all bowel cancer patients under 50 are systematically tested.
Bowel Cancer UK submitted the FOI request in November 2014 to every NHS trust in England, health board in Scotland and health and social care trust in Northern Ireland to establish the number of trusts/health boards which were implementing the testing for all bowel cancer patients under 50, as mandated by the Royal College of Pathologists. Lynch syndrome is responsible for around one in 12 cases of bowel cancer in people aged under 50.
Dr Suzy Lishman, President of the Royal College of Pathologists, said, “This research is encouraging as it shows that our guidelines may have had some impact already on testing for Lynch syndrome in patients diagnosed under the age of 50. However, there is considerable variation in the approach to testing. Testing is now mandated by the Royal College of Pathologists as part of the core dataset for pathology and is a required reflex test for this group of young patients. We would urge all trusts to perform the screening test for Lynch syndrome in bowel cancer patients under 50 and to adopt a more consistent approach to the testing.”
Deborah Alsina, Chief Executive of Bowel Cancer UK said, “We welcome the fact that some trusts and health bodies have implemented this guidance, but it is concerning that variation still remains. The disparity between hospital trusts and health boards in England, Wales and Scotland is even greater than we anticipated.”
“It’s crucially important that all bowel cancer patients under 50 are offered genetic testing at diagnosis as it could affect both surgical and chemotherapy decision making. Yet currently it is normally done after treatment has ended, if at all. Not only that, but appropriate surveillance needs to be arranged as patients with Lynch syndrome are at greater risk of recurrence. Additionally, as Lynch syndrome is a genetic condition, it can have implications for other family members who may be at risk of developing bowel cancer so family members should also be tested to identify any others with the condition.”
Andy Sutton, the father of teenager Stephen Sutton who sadly died last year from bowel cancer, is all too aware of the need for systematic Lynch syndrome testing. Andy was diagnosed with bowel cancer twice – in 1989 at the age of 31 and 20 years later in 2009. It was only second time round that Andy was tested for Lynch syndrome, which was inherited by his son, Stephen.
Andy said, “If I had been genetically tested after the first diagnosis and given regular surveillance screening, it might have been possible to have prevented bowel cancer developing second time around. That’s why I’m supporting Bowel Cancer UK’s call for everyone under the age of 50 who is diagnosed with bowel cancer to have testing for Lynch syndrome, it had a tragic impact on our family and I want to save others from going through the same experience.”
Dr Kevin Monahan, Consultant Gastroenterologist and General Physician, Family History of Bowel Cancer Clinic, West Middlesex University Hospital says: “Anyone under 50 who is diagnosed with bowel cancer is eligible for testing but it is not always offered. In the first instance, discuss testing for Lynch syndrome with your consultant or your GP”
Bowel Cancer UK is calling for urgent action to be taken:
1. We would urge NHS England and Wales to adopt a similar approach to NHS Scotland and establish a nationwide initiative to ensure a consistent, systematic approach to screening for Lynch syndrome as mandated by the Royal College of Pathologists.
2. All CCGs must commission to reflect the RCPath cancer dataset thus ensuring providers are compliant with this cancer dataset.
3. Accreditation of pathology departments should be linked to compliance with the core minimum dataset which may be used as a metric.
Nearly two years ago Bowel Cancer UK launched the Never Too Young campaign to increase early diagnosis and improve treatment and support for people diagnosed with bowel cancer under the age of 50. Central to that work was a survey which helped understand the experiences of younger people with bowel cancer. Some of the campaign successes so far include:
Bowel Cancer UK and clinical experts are urging all hospitals across the UK to implement Lynch syndrome testing at diagnosis for everyone with bowel cancer under the age of 50. Lynch syndrome is an inherited condition which causes over 1,000 cases of bowel cancer in the UK every year, many of them in people under the age of 50. However, fewer than 5% of people with Lynch syndrome in the UK have been diagnosed.
Testing everyone with bowel cancer under the age of 50 at diagnosis for Lynch syndrome will help identify family members who may carry Lynch syndrome and be at risk of bowel cancer. It has been shown to be cost effective for the NHS, and is recommended by the Royal College of Pathologists and British Society of Gastroenterologists. It is also a key recommendation in our Never Too Young campaign.
People with Lynch syndrome should then access regular surveillance screening, which can detect bowel cancer in the early stages and has been shown to reduce mortaility from bowel cancer by 72%.
Despite this, testing and surveillance screening are patchy across the UK. A letter in the Daily Telegraph (13 November 2014) from eight leading clinical experts supports our call for all hospitals to implement Lynch syndrome testing at diagnosis for people with bowel cancer under the age of 50.
The letter and signatories are as follows:
There are more than 1,000 cases of bowel cancer a year that are attributable to Lynch syndrome (LS), many under the age of 50. LS is an inherited condition that predisposes individuals to bowel and other cancers, with a lifetime risk of around 70 per cent. Yet in the UK we have identified fewer than 5 per cent of families with LS. The family of Stephen Sutton, who was diagnosed with bowel cancer and whose father has LS, was one of them. It is a consistently under-recognised, under-diagnosed and inadequately treated condition.
Both the Royal College of Pathologists and the British Society of Gastroenterology recommend testing everyone with bowel cancer under the age of 50 at diagnosis to help us to identify family members who may carry LS and be at risk of bowel cancer. Yet testing is patchy. We urge all hospitals across the UK to implement this guidance.
This testing would mean people at risk could access surveillance programmes for regular colonoscopies, helping detecting bowel cancer early but also preventing it.
Patient groups such as Bowel Cancer UK are in support. A recent NHS study found that LS testing at diagnosis for everyone under 50 with bowel cancer would be cost effective enough to have been approved by NICE. The evidence is overwhelming. We must end this postcode lottery.
Dr Suzy Lishman, President, The Royal College of Pathologists
Professor Malcolm Dunlop MD FRCS FMedSci FRSE, Colon Cancer Genetics Group and Academic Coloproctology, Head of Colon Cancer Genetics, Institute of Genetics & Molecular Medicine
Professor D Gareth Evans MD FRCP, Professor of Clinical Genetics and Cancer Epidemiology and Consultant Geneticist, University of Manchester
Commenting on the letter from clinical experts, Deborah Alsina, CEO of Bowel Cancer UK, said:
“The Royal College of Pathologists recently produced best practice guidelines recommending everyone with bowel cancer under the age of 50 should be tested for Lynch syndrome at diagnosis. Speedy implementation is vital as testing is currently patchy at best and if people are tested at all, it is often after treatment ends. Yet a diagnosis of Lynch syndrome can affect treatment decisions. We are therefore calling for all UK hospitals to implement this guidance swiftly.”
“This will also help to identify the risk to other family members who may also carry Lynch syndrome and who may be at higher risk of developing bowel cancer. Once identified, people at risk, including those diagnosed who have a greater chance of recurring or developing another linked cancer, should have access to surveillance programmes including regular colonoscopies. This will help to ensure bowel cancer is either prevented or detected early.”
Bowel Cancer UK will be writing to all Clinical Commissioning Groups and Health Trusts in the UK asking them if they have implemented systematic Lynch syndrome testing, and we will report back on the responses. In the meantime, please share our infographic on the subject on social media to help raise awareness of the issue.
Lynch Syndrome (LS), formerly known as Hereditary non-polyposis colorectal cancer (HNPCC) is a familial cancer syndrome; affected individuals have disease-associated mutations in one of a number of key genes involved in normal DNA repair processes (most commonly the MLH1, MSH2, MSH6 and PMS2 genes). This results in a significantly increased risk of developing certain forms of cancer, notably colorectal (bowel) cancer but also endometrial and ovarian cancers and a number of others.
Teenager Stephen Sutton, who raised millions of pounds for cancer research, had a family history of the syndrome. The test for this condition is used in some UK hospitals but has not been rolled out nationally. It is offered to all bowel cancer patients in Denmark, and to patients under the age of 70 in Norway and the Netherlands.
New research published as a formal Heath Technology Assessment has examined the efficacy and cost-effectiveness of alternative strategies to diagnose LS in patients with early-onset colorectal cancer – those younger than 50, 60 or 70 years of age.
Identifying LS has important health benefits for the patients – allowing appropriate close monitoring or preventative treatments for different forms of cancer as well as recurrences of colorectal cancer; for example, removal of the womb or ovaries in women. Moreover, cascade testing of close relatives can also identify family members at high risk of the same cancers who would benefit from risk reduction strategies.
The researchers compared the alternative approaches of microsatellite instability (MSI) testing or immunohistochemistry (IHC), including economic data. Analysis of the available evidence showed that testing for LS newly-diagnosed colorectal cancer patients aged under 70 years is indeed cost-effective. No specific method emerged as a clear ‘gold-standard’ for testing but the most cost-effective approach was found to be the use of MSI and BRAF mutation testing; cascade testing of at-risk family members was recommended for all strategies.
Efforts to review the alternative techniques and develop a consensus optimal strategy for national implementation have been in progress for many years.
The new HTA findings, combined with a new clinical classification scheme for genetic variants associated with LS released by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) earlier this year, should underpin policy changes that will increase the numbers of people identified with LS and prevent cancers.
Dr Ian Frayling of Cardiff University‘s Institute of Medical Genetics, one of the researchers, told the BBC: “Now the cost of genetic testing is coming down there is a good argument for younger bowel cancer patients to be screened. It will save lives and save money for the NHS”.
Looking further ahead, he and colleagues recommended new research into the cost-effectiveness of testing for LS in younger patients with newly diagnosed endometrial or ovarian cancer, and of the value of treatment with aspirin to reduce the risk of future cancers.
Deborah Alsina, chief executive of Bowel Cancer UK, said while bowel cancer is relatively rare in people under 50, 550 people in this age group lose their lives to the cancer each year.
“It’s critical that more lives are saved by ensuring people gain access to the screening surveillance they need, so that bowel cancer can be ruled out first, not last, in younger patients.”
Hayley Hovey was 23 weeks’ pregnant with her first baby when she suddenly woke in the middle of the night with a sharp, shooting pain in her side.
She visited her GP’s out-of-hours service but was reassured to hear her baby’s heartbeat and be told all was well. The pain was probably ‘ligament strain’ caused by the weight of the growing baby. ‘I was ecstatic to be having a baby – I’ve always wanted to be a mum,’ says Hayley, 34. ‘All my scans showed my baby was healthy, so I didn’t think anything more about that pain.’
She now knows it was the first sign there was a grave threat to her baby’s life, and her own. Four weeks later her daughter, Autumn, was born prematurely and later died. Then Hayley was found to have bowel cancer.
Doctors now think Autumn’s death was linked to her mother’s cancer, with a blood clot breaking away from the tumour, damaging Hayley’s placenta and cutting off the food supply to her unborn baby.
However, it took four months after Autumn’s death for Hayley to be diagnosed. The problem was her age – she was ‘too young’ for bowel cancer to be considered.
Hayley, who lives in Fareham, Hants, with her husband Paul, a 35-year-old IT consultant, says: ‘Looking back, I had textbook symptoms – exhaustion, intermittent stomach pains, increasingly bad diarrhoea, blood in my stools and bleeding.
The disease is Britain’s second-biggest cancer killer, claiming 16,000 lives a year. The number of under-50s diagnosed has been gradually rising – to around 2,100 a year.
But a recent survey by the charity Bowel Cancer UK of patients under 50 found that 42 per cent of the women had visited their GP at least five times before being referred for tests.
Indeed, Hayley, a supply planner for an IT firm, was examined five times by different doctors and midwives, who all missed her symptoms, despite a golf ball-sized lump appearing on her stomach after her pregnancy. By the time she was diagnosed, Hayley had stage three to four cancer, meaning the tumour had broken through her bowel wall.
She had to undergo a seven-hour operation to remove the 6cm growth, followed by six months of chemo and radiotherapy.
But her experience is not uncommon, says Deborah Alsina, chief executive of Bowel Cancer UK: ‘We hear from many younger people who express frustration at not getting a diagnosis and support.’
‘Bowel cancer is often associated with older patients over 50 – but younger people can, and do, regularly get it, as the tragic story of Stephen Sutton recently highlighted,’ adds Kevin Monahan, consultant gastroenterologist at West Middlesex University Hospital, London.
Stephen Sutton, 19, raised more than £3million during his three-year battle against multiple tumours
Stephen Sutton, the 19-year-old fundraiser who died last week from the disease, told the Mail earlier this month of his anger that he was not diagnosed for six months after his symptoms started. This was despite his family history of Lynch syndrome, a genetic condition that raises the risk of bowel cancer.
‘If it had been caught earlier, it could have led to a better prognosis,’ he said. Hayley, too, eventually discovered she had Lynch syndrome.
Bowel cancer is very treatable if detected early – 93 per cent of patients who are found to have a small tumour on the bowel wall live for five years or more. Yet only 9 per cent of cases are diagnosed at this stage – most are diagnosed at stage three. So, the overall five-year survival rate for bowel-cancer patients is just 54 per cent.
Because patients and many doctors assume that young people won’t get bowel cancer, they are particularly likely to have advanced-stage tumours at the time of diagnosis.
Bleeding or blood in faeces
A change in bowel habits lasting more than three weeks
Unexplained weight loss
See bowelcanceruk.org.uk; beatingbowelcancer.org (phone 08450 719 301); and familyhistorybowelcancer.wordpress.com/
Cancer charities are campaigning to improve diagnosis for all ages – they want new diagnostic guidelines for GPs and earlier screening procedures.
Sean Duffy, NHS England’s national clinical director for cancer, says: ‘The UK lags behind much of Europe in terms of survival from bowel cancer. We need to change this, and this includes identifying it better in patients under 50.’
National GP guidelines state only patients aged 60 and over should be automatically referred to hospital for tests if they have one symptom. Patients aged 40 to 60 must exhibit two or more symptoms.
For under 40s, there is often an assumption the symptoms must be something else, says Mark Flannagan, chief executive of the charity Beating Bowel Cancer. ‘We’ve had patients with red-flag symptoms – such as blood in their stools – being told “you’ve got IBS” or “you’re too young to have cancer” by their GPs.’
Four weeks after Hayley’s initial scare, she was unable to feel her baby moving. Tests revealed Autumn had stopped growing, and she had to be delivered by emergency caesarean. After her birth, in July 2011, she was taken to a specialist neo-natal unit at Southampton General Hospital but died in hospital a few weeks later.
Two weeks afterwards, Hayley experienced more shooting pains. With her pregnancy bump gone, there was also a noticeable lump on the side of her waist. Her midwife said it was probably an infection, and Hayley was given antibiotics.
But her health deteriorated rapidly and she had to take six weeks off work with exhaustion, which her GP put down to depression.
Within three months of Autumn’s death, Hayley was suffering from nausea and abdominal pain.
Unable to get a GP’s appointment, she went to A&E but was told the lump was possibly an infection related to her caesarean. Doctors performed a cervical smear test (which was subsequently lost) and sent her home with paracetamol.
Stephen Sutton with his mother Jane whilst Prime Minister David Cameron visited him
‘I got the impression they didn’t take me very seriously,’ she recalls.
Soon after, she was vomiting up to ten times a day, feeling dizzy and weak, passing blood and experiencing chronic diarrhoea. At an emergency GP appointment, she was examined by a different doctor who immediately referred her to hospital; after several days of tests, she was diagnosed with cancer.
Four days before Christmas, Hayley underwent surgery. ‘We thought we’d be enjoying our first Christmas as a family, but instead I was in hospital, grieving for the loss of our little girl and terrified about the future,’ she recalls. ‘My treatment might have been less of an ordeal if my cancer had been picked up sooner. It makes me quite angry to think if I’d been 60, it would have been picked up more quickly.’
But even obvious symptoms are often missed by doctors, says Mr Flannagan. ‘I am not blaming GPs, but we need to not be shy of pointing out where things are going wrong. The default position should be for a GP to rule out cancer, just to be safe.’
‘It can also be problematic if patients don’t have obvious symptoms such as bleeding’, says Dr Monahan. ‘They may instead have vaguer symptoms such as tiredness, unexplained weight loss or abdominal pain, which could be attributed to being symptoms of other conditions such as irritable bowel syndrome or Crohn’s disease.’
Public awareness is also an issue. A survey in March by health insurer AXA PPP found nearly half of men couldn’t name one symptom of bowel cancer.
Indeed, Martin Vickers, 49, had never heard of it before his diagnosis in 2008. ‘I was totally shocked,’ says the father of four, who lives in Burton-on-Trent with wife Andrea, 48. ‘I didn’t know bowel cancer existed. It was hugely traumatic.’
Martin visited his GP five times in nine months with extreme tiredness and loose stools. His symptoms were attributed to stress – his mother had recently died and he has a high-pressure job as head of capital investment for Cambridge and South Staffordshire Water – and then IBS.
Joining friends and family to complete a Guinness Book of Records challenge creating hearts with hands
‘But I knew something wasn’t right,’ says Martin. ‘It was instinctive.’ He was finally diagnosed with stage three bowel cancer in November 2008, after his GP did an internal examination and felt a lump.
Martin underwent three months of chemotherapy and radiotherapy, followed by surgery, another six months of chemotherapy and a second operation. He now has to use a colostomy bag but has been in remission for five years.
Currently, screening is only available to people aged 60-plus. They are sent home tests, which involve sending a stool sample to a lab. But the Department of Health is now looking at a new procedure, bowel scope screening, which involves a partial colonoscopy -examining only the lower bowel.
A major UK trial of 55 to 64 year olds showed that people screened this way were 43 per cent less likely to die from bowel cancer, and 33 per cent less likely to develop it.
This is because the procedure is usually successful at detecting small growths known as polyps, which can become cancerous.
The screening – which would be offered to everyone aged 55 and over – is now being piloted. Campaigners hope it will be made available nationally by 2016.
‘This is a really important development and should make a big difference to bowel cancer outcomes,’ says Dr Monahan, who runs the Family History of Bowel Cancer clinic at West Middlesex University Hospital, specialising in hereditary components of the disease.
It won’t, however, help younger patients such as Hayley. Before her chemotherapy, she and Paul had nine embryos frozen via IVF. However she is worried she may pass on Lynch syndrome, so the couple are considering what to do.
But she says: ‘I am still here, I have a life ahead of me – and I hope my story will help others to be diagnosed in time.’
A history of polyposis and familial colorectal cancer
(Link to full article can be found here)
On the 25 September 2012 a meeting was held in Central London, convened by the History of Modern Biomedicine Research Group of Queen Mary, University of London, and funded by the Wellcome Trust. Assembled were many of the men and women whose research was at the forefront of the breakthroughs that led to the identification of genes for familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) (Lynch Syndrome) in the 1990s.
One of the most significant locations for early research into hereditary bowel cancer was St Mark’s Hospital in London, where surgeon John Percy Lockhart-Mummery (1875–1957) and pathologist Dr Cuthbert Dukes (1890–1977) were based. As Ms Kay Neale explained: ‘St Mark’s Polyposis Registry started in 1924 as a result of John Percy Lockhart-Mummery having an interest in family diseases and Dr Dukes having an interest in polyps turning into cancer.’ The Registry’s success was helped enormously by the work of Dick (later Dr) Bussey, who, aged just 17, started a meticulous system for recording patients with FAP, a condition that had first been noted in the medical literature as early as 1882. Neale elaborated on the spread of the Registry’s impact beyond the UK: ‘Dukes, of course, would lecture and publish in the journals of the day and so people would send pathological slides or descriptions of cases of polyposis from all over the world, and Dr Bussey would record them all and catalogue them.’ Fast forward to the 1980s when Sir Walter Bodmer became Director of Research at the Imperial Cancer Research Fund (ICRF) and, during the meeting, he recalled how in 1984 he established a St Mark’s Unit at the ICRF for all aspects of colorectal cancer, as research in familial cancer began to take more shape. The context for this growth in familial cancer research during the 1980s is discussed by Professor Tim Bishop in his introduction to the publication, along with several seminar participants who reflect on the work of the UK’s Cancer Family Study Group.
Representing a transatlantic viewpoint, Professor Jane Green from Canada moved the story into the 1990s and to HNPCC. A world away from the research lab, she tried to find familial links amongst cancer patients: ‘I spent many hours on roads in Newfoundland going to different small communities and talking to people in their homes. Every time somebody said, I’ll speak to my grandmother because she knows more of the history,’ or ‘You need to know about that other part of the family’ and they would contact them … As I put the pedigrees together they were very, very interesting.’ Her informal conversations revealed linkages, the understanding of which would be critical to the international effort that identified the MSH2 and MLH1 HNPCC-related genes in 1993. Like Jane Green’s families, patients from St Mark’s Polyposis Register were critical in providing DNA samples that helped identify APC, the gene for polyposis in 1991.
These and many other stories from the scientists, clinicians and others involved in this significant research can be read in more depth in the published, annotated transcript of this Witness Seminar. This volume is free to download from the Group’s website as a PDF document.
Emma M Jones, Alan YabsleyHistory of Modern Biomedicine Research Group Queen Mary, University of London Mile End Road London E1 4NS United Kindom
Analysis from a recent study has found that loading up on snack foods may increase cancer risk in individuals with an inborn susceptibility to colorectal and other cancers. Published early online in Cancer, a peer-reviewed journal of the American Cancer Society, the study suggests that an eating pattern low in snack foods could help these individuals — who have a condition called Lynch syndrome — lower their risk.
Lynch syndrome is an inherited condition characterized by a high risk of developing colorectal cancer, endometrial cancer, and other cancers at an early age. The syndrome is caused by mutations in genes involved with repairing DNA within cells.
Numerous studies have investigated associations between certain foods and colorectal cancer, and now there is general agreement that red and processed meats and alcohol consumption can increase individuals’ risk. Only a few studies have evaluated lifestyle factors and colorectal cancer in patients with Lynch syndrome, though. To investigate, Akke Botma, PhD, MSc, of the Wageningen University in the Netherlands, and her colleagues collected dietary information from 486 individuals with Lynch syndrome. During an average follow-up of 20 months, colorectal polyps (precancerous lesions) were detected in 58 people in the study.
“We saw that Lynch syndrome patients who had an eating pattern with higher intakes of snack foods — like fast food snacks, chips, or fried snacks — were twice as likely to develop these polyps as Lynch syndrome patients having a pattern with lower intakes of snack foods,” said Dr. Botma.
The findings suggest that certain dietary patterns have an influence on the development of polyps in individuals with Lynch syndrome. “Unfortunately, this does not mean that eating a diet low in snack foods will prevent any polyps from developing, but it might mean that those Lynch syndrome patients who eat a lot of snack foods might have more polyps than if they ate less snack foods,” said Dr. Botma. Because the study is observational, other studies are needed to confirm the results.
Previous work from the group revealed that smoking and obesity may also increase the risk of developing colorectal polyps among individuals with Lynch Syndrome. Thus, even though they may have inherited a very high risk of developing cancer, it may be possible to affect this risk by adopting a healthy lifestyle, including a healthy diet.
Akke Botma, Hans F. A. Vasen, Fränzel J. B. van Duijnhoven, Jan H. Kleibeuker, Fokko M. Nagengast and Ellen Kampman. Dietary patterns and colorectal adenomas in Lynch syndrome : The GEOLynch Cohort Study. Cancer, 2012; DOI: 10.1002/cncr.27726
Lynch Syndrome is an inherited cancer syndrome which causes up to 1 in 20 cases of bowel cancer in Ireland, that is equivalent to over 100 cases annually in the Republic of Ireland alone. It is also an important cause of multiple cancers outside the bowel including endometrial, ovarian, and urinary tract cancers.
Prevention of cancer in people at high risk depends on the accurate identification of families with this condition. However it is estimated that over 90% of families remain unidentified. Currently there are two clinical genetics centres in Ireland, in Dublin and Belfast. Unfortunately there is only limited access to genetic testing particularly in the Republic of Ireland where testing for Lynch Syndrome may only be requested from within the genetics department in Dublin. Thus it may be argued that much more could be done to improve the management of this condition in Ireland.
Some published data indicates that Lynch Syndrome may account for up to 5% of colorectal cancer in Ireland, thus this has a highly clinically significant impact.
A series of published abstracts from international medical conferences have been reproduced below which summarise the available academic work on Lynch Syndrome in Ireland.
Screening an Irish cohort with colorectal cancer for Lynch Syndrome using immunohistochemistry for mismatch repair proteins
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 10547 © 2007 American Society of Clinical Oncology. D. G. Power, M. P. Farrell, C. B. Muldoon, E. Fitzpatrick, C. Stuart, D. Flannery, M. J. Kennedy, R. B. Stephens and P. A. Daly St James’s Hospital, Dublin, Ireland Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. Published on Meeting Library (http://meetinglibrary.asco.org)
Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds.
J Clin Oncol 30: 2012 (suppl 34; abstr 431) Author(s): Michael P. Farrell, David J. Hughes, Jasmin Schmid, Philip S. Boonstra, Bhramar Mukherjee, Margaret B. Walshe, Padraic M. Mac Mathuna, David J. Gallagher; Mater Private and Mater Misericordiae University Hospital, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Biostatistics, University of Michigan, Ann Arbor, MI; High Risk Colorectal Family Clinic, Mater Misericordiae University Hospital, Dublin, Ireland; Mater Private Hospital and Mater Misericordiae University Hospital, Dublin, Ireland
Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Veiland and Huang bivariate model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Genetic anticipation was present in this cohort of LS families, emphasizing the importance of early-onset screening. An additional 60 LS kindreds are under review and updated data will be presented at the meeting. POE effect: comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome associated malignancies. Affected mothers Affected fathers P value Unique parent N = 14 N = 13 0.28 Mean = 48.8 Mean = 53.6 Range = 27-73 Range = 36-85 All offspring N = 24 N = 30 0.67 Mean = 40.4 Mean = 41.6 Range = 23-72 Range = 23-60 Female offspring N = 6 N = 15 0.75 Mean = 42.5 Mean = 41.06 Range = 31-64 Range = 27-58 Male offspring N = 18 N = 15 0.94 Mean = 39.77 Mean = 40.07 Range 23-72 Range = 20-60 P value female vs male offspring 0.604 0.95 ________________________________________ Source URL: http://meetinglibrary.asco.org/content/106059-133 Published on Meeting Library (http://meetinglibrary.asco.org) Home > 88749-115 ________________________________________ 88749-115
Breast cancer in Irish families with Lynch syndrome.
J Clin Oncol 30, 2012 (suppl 4; abstr 413) Author(s): E. J. Jordan, M. P. Farrell, R. M. Clarke, M. R. Kell, J. A. McCaffrey, E. M. Connolly, T. Boyle, M. J. Kennedy, P. J. Morrison, D. J. Gallagher; Mater University Hospital, Dublin, Ireland; St. James Hospital, Dublin, Ireland; Mater University Hospital , Dublin , Ireland; Belfast City Hospital HSCTrust, Belfast, Northern Ireland Background: Breast cancer is not a recognised malignant manifestation of Lynch Syndrome which includes colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland, and a genotype phenotype correlation was investigated. One kindred was omitted due to the presence of a biallelic MMR and BRCA1 mutation. The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in 16 pedigrees was as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Six MSH2 mutations and 1 MSH6 mutation were identified in the 7 Lynch syndrome kindreds. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. Final results of immunohistochemistry for mismatch repair protein expression on breast cancer samples are pending and will be reported at the meeting. One breast cancer has been tested to date and demonstrated loss of MSH2 protein expression in an individual carrying an MSH2 mutation. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All reported breast cancer cases were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds. ________________________________________ Source URL: http://meetinglibrary.asco.org/content/88749-115
Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.
Fam Cancer. 2012 Sep;11(3):509-18. doi: 10.1007/s10689-012-9544-4.Farrell MP, Hughes DJ, Berry IR, Gallagher DJ, Glogowski EA, Payne SJ, Kennedy MJ, Clarke RM, White SA, Muldoon CB, Macdonald F, Rehal P, Crompton D, Roring S, Duke ST, McDevitt T, Barton DE, Hodgson SV, Green AJ, Daly PA. Source Department of Cancer Genetics, Mater Private Hospital, Dublin 7, Ireland. firstname.lastname@example.org
Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic. PMID: 22773173 [PubMed – indexed for MEDLINE]
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than Hereditary Non Polyposis Colorectal Cancer cohorts
Ulster Med J. 2008 January; 77(1): 25–30. PMCID: PMC2397009 Lisa A Devlin,1 Colin A Graham,1 John H Price,2 and Patrick J Morrison1
Objective To determine and compare the prevalence of MSH6 (a mismatch repair gene) mutations in a cohort of families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and in an unselected cohort of endometrial cancer patients (EC). Design Two patient cohorts participated in the study. A cohort of HNPCC families who were known to the Regional Medical Genetics department, and an unselected cohort of patients with a history of EC. All participants received genetic counselling on the implications of molecular testing, and blood was taken for DNA extraction with consent. All samples underwent sequencing and Multiple Ligation probe analysis (MLPA) for mutations in MSH6. Populations DNA from one hundred and forty-three probands from HNPCC families and 125 patients with EC were included in the study. Methods Molecular analysis of DNA in all participants from both cohorts for mutations in MSH6. Outcome measures Prevalence of pathogenic mutations in MSH6. Results A truncating mutation in MSH6 was identified in 3.8% (95% CI 1.0–9.5%) of patients in the endometrial cancer cohort, and 2.6% (95% CI 0.5–7.4%) of patients in the HNPCC cohort. A missense mutation was identified in 2.9% and 4.4% of the same cohorts respectively. No genomic rearrangements in MSH6 were identified. Conclusion MSH6 mutations are more common in EC patients than HNPCC families. Genomic rearrangements do not contribute to a significant proportion of mutations in MSH6, but missense variants are relatively common and their pathogenicity can be uncertain. HNPCC families may be ascertained through an individual presenting with EC, and recognition of these families is important so that appropriate cancer surveillance can be put in place. Keywords: Endometrial, Cancer, MSH6, HNPCC
A new study1 that combines genetic information on bowel cancer with NHS patient outcome data has found a link between family history of the disease and a better chance of survival, published in the British Journal of Cancer.
Cancer Research UK scientists, based at the University of Leeds, in collaboration with the National Cancer Intelligence Network (NCIN), matched the genetic data2 of nearly 11,000 bowel cancer patients with data from the National Cancer Data Repository (NCDR) on treatment and survival.
And by tracking the survival of these bowel cancer patients they found that the 1,700 people (16 per cent) with a family history of the disease were 11 per cent less likely to die from bowel cancer within 5 years of diagnosis than patients who had no family history of the disease3.
The scientists believe the better prognosis for those with a family history may be linked to the fact that these patients were more likely to have right-sided tumours, that are biologically different to other tumour types, which may respond better to treatment.
Dr Eva Morris, a Cancer Research UK funded scientist at the University of Leeds, and lead author of the research, said: “Our study has found a relationship between family history of bowel cancer and a higher chance of survival.
“Although we haven’t been able to determine exactly why this is the case, it does demonstrate how we can use data that we already routinely collect to help us develop a better understanding of bowel cancer and its genetic causes.
“As datasets such as the NCDR expand and collect more detailed information this opens up the possibility of using this data to help develop better targeted treatments for patients, based upon their individual genetics.”
Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This is another important step forward in our understanding of bowel cancer. Now we need to find out more about what’s causing this difference. Studies like this, which link genetic data to detailed patient information, may help us develop a more personalised approach to treating cancer in the future.
“Survival from bowel cancer is best when it’s diagnosed and treated in the early stages, so anyone who notices possible symptoms of the disease – blood in stools, or changes to bowel habits lasting longer than three weeks should get this checked out. If you think you may have a family history of bowel cancer it’s worth discussing this with your GP.”