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We support Lynch syndrome testing and bowel cancer in people under 50


https://i1.wp.com/www.bowelcanceruk.org.uk/media/414473/lynch_syndrome_and_bowel_cancer_november_2014.jpgBowel 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:

Dear Editor

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 Kevin Monahan, Consultant Gastroenterologist and General Physician at Family History of Bowel Cancer Clinic, West Middlesex University Hospital (WMUH), London

Professor Sue Clark, Chair of the Colorectal Section of the British Society of Gastroenterology, Consultant Colorectal Surgeon, St Mark’s Hospital

Professor John Schofield, Consultant Pathologist, Cellular Pathology Department, Maidstone Hospital and Kent Cancer Centre

Dr Suzy Lishman, President, The Royal College of Pathologists

Professor Ian Tomlinson, Professor of Molecular and Population Genetics, Group Head / PI and Consultant Physician, Wellcome Trust Centre for Human Genetics

Professor Huw JW Thomas, Consultant Gastroenterologist, Family Cancer Clinic, St Mark’s Hospital, London

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.

Why do GPs fail to spot bowel cancer in young people like Stephen – until too late? (From the Daily Mail)


   Why do GPs fail to spot bowel cancer in young people like Stephen – until too late? (From the Daily Mail)

  • Stephen Sutton died after a four-year battle with bowel cancer
  • 19-year-old raised millions for the Teenage Cancer Trust before his death
  • Number of under-50s diagnosed is gradually rising to around 2,100 a year

By Judith Keeling

Hayley was 'too young' for bowel cancer to be considered

Hayley was ‘too young’ for bowel cancer to be considered

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, 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.

What to watch for

Bleeding or blood in faeces

A change in bowel habits lasting more than three weeks

Exhaustion

Unexplained weight loss

Abdominal pain

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

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

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.

 

Beating bowel cancer – The bottom line

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.’

Read more: http://www.dailymail.co.uk/health/article-2633287/Why-GPs-fail-spot-bowel-cancer-young-people-like-Stephen-late.html#ixzz32TNCY2Lm

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Guest Blog: Wellcome Witnesses to Contemporary Medicine series, ‘Clinical Cancer Genetics: Polyposis and Familial Colorectal Cancer c.1975–c.2010’.


Polyposis (carpeting a rectum after a previous ileocolonic anastamosis)

Polyposis (carpeting a rectum after a previous ileocolonic anastamosis)

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.

http://www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/vol46/

Emma M Jones, Alan Yabsley

History of Modern Biomedicine Research Group
Queen Mary, University of London
Mile End Road
London E1 4NS
United Kindom

New scheme to routinely test patients for inherited cancer genes


CRUK LogoNew scheme to routinely test patients for inherited cancer genes

A new research programme will lay the foundations for routine testing for inherited cancer genes in patients with the disease.

Changes in certain genes, known as cancer predisposition genes, greatly increase the chances of a person developing cancer. Knowing whether a patient carries such a gene can affect decisions as to how treat them.

There are almost 100 known cancer predisposition genes, but at present testing for them in the UK is done on an ad hoc basis, with patients referred to a genetics service if they are suspected of having an ‘inherited’ cancer.

Under the new Mainstreaming Cancer Genetics programme, initially involving patients with breast or ovarian cancer patients at the Royal Marsden in London, screening for cancer predisposition genes will be done routinely.

The genetic testing will be managed by the patient’s cancer doctor, rather than by referring them to a genetics clinic. It will be rolled out to patients with other cancer types over the next few years.

The ultimate aim is to develop a ‘toolkit’ to share with other parts of the NHS, allowing them to set up similar services for patients.

The programme is being led by a team at The Institute of Cancer Research, in partnership with The Royal Marsden, Illumina Inc, and the Wellcome Trust Centre for Human Genetics, which provided £2.7m of funding.

Professor Nazneen Rahman, head of genetics at the Institute of Cancer Research (ICR), said it was “very important” for doctors to know if a inherited change in a patient’s genetic blueprint had caused their cancer.

Testing allows for more personalised treatment, since a patient with a cancer predisposition gene may face a higher risk of developing a subsequent second cancer.

Knowing they have the gene gives them the option of having more comprehensive surgery, taking different medicines, or receiving extra monitoring.

The screening programme could also provide useful information about the cancer risks of a patient’s relatives.

“Sometimes a relative is found to also have an increased risk of cancer and screening or preventative measures can be employed,” Dr Rahman added.

“Just as frequently, testing provides the reassuring news that a relative is not at increased risk of cancer and does not need interventions.”

The new programme will use a new test, developed in conjunction with Illumina Inc, that takes advantage of new sequencing methods.

The TruSight Cancer panel can analyse 97 cancer predisposition genes within a few weeks for the cost of a few hundred pounds and will be ready for use in the clinic in 2014.

Professor Peter Johnson, Cancer Research UK‘s chief clinician, said researchers now have a wealth of information about the inherited gene faults that increase a person’s cancer risk, and this knowledge can help tailor treatments for patients whose cancers are linked to these mutations.

“This exciting new initiative will help embed genetic testing into routine NHS cancer care, and hopefully allow more cancer patients to benefit from such testing – and more personalised care – in the future,” he added.

Patients will be tested for inherited faults in their body’s DNA that might be linked to their cancer, rather than faults in the tumour itself.

That will complement initiatives such as Cancer Research UK’s own stratified medicine programme, which aims to analyse the faulty genes driving a patient’s tumour, paving the way for doctors to tailor treatments to their type of cancer.

“Together, these programmes will help revolutionise the way cancer is managed in the NHS, and bring forward the day when all cancers are cured,” Professor Johnson added.

Association of the insulin-like growth factor 1 (IGF1) microsatellite with predisposition to colorectal cancer


Gut 2011;60:A116 doi:10.1136/gut.2011.239301.245
  • Neoplasia and cancer pathogenesis

* Association of the insulin-like growth factor 1 microsatellite with predisposition to colorectal cancer

K J Monahan *, S Spain, H J Thomas, I P Tomlinson

Gastroenterology, West Middlesex University Hospital, London, Cancer Medicine, Imperial College, London,Molecular and Population Genetics, Cancer Research UK, London, UK

Abstract

Introduction IGF1 may be important for colorectal cancer risk because of its role in cell growth and differentiation. High IGF1 serum levels have been associated with increased risk of colorectal cancer. Variations in these serum levels have been associated with a CA repeat microsatellite 1 kilobase upstream of the transcription start site. We sought to determine the association of germline variation of the IGF1 gene with colorectal cancer predisposition by performing a large case-control study.

Methods Genescan 500 was used to differentiate alleles of the IGF1 microsatellite among 2143 colorectal cancer cases (enriched for family history) and 1715 controls from the CORGI (COloRectal Gene Identification) study, with subsequent 100% confirmation of about 5% of genotypes by direct sequencing. Associations of genotypes with the following clinicopathological features were tested: sex; site of tumour; Dukes stage; age of onset; presence of adenomas. Using genotype data obtained from the Hap550 platform by colleagues1 plus the genotypes at the insertion/deletion, we reconstructed haplotype blocks around the IGF1 gene in the controls using 68 tagging SNPs.

Results All the alleles confer increased risk for colorectal neoplasia except ‘192′ (192 copies of CA repeat), which is a protective allele (allelic OR for ‘192′ =1.199; 95% CI 1.09 to 1.32; p = 0.000152). The population attributable risk (PAR) for the risk ‘allele’ (ie, where ‘X’=not ‘192′) is 2.94%. The risk alleles occurred more frequently in more advanced Dukes’ stage tumours (p=0.039, χ2). Several SNPs in close linkage disequilibrium with IGF1 are also significantly associated with colorectal neoplasia risk.

LD IGF1

LD Plot IGF1

IGF1 p value

Conclusion This study demonstrates a novel association of IGF1 microsatellite with colorectal cancer risk. The association is stronger with advanced stage colorectal cancers, and in colonic rather than rectal cancers. This microsatellite is in linkage disequilibrium with other significant SNPs in the promoter region of this gene.

P21 / CDKN1A germline variation and low penetrance predisposition to colorectal cancer


Gut 2011;60:A116-A117 doi:10.1136/gut.2011.239301.246

CDKN1A germline variation and low penetrance predisposition to colorectal cancer

K J Monahan *, S Spain, H J Thomas, I P Tomlinson

Family History of Bowel `Cancer Clinic, West Middlesex University Hospital, London, UK; Cancer Medicine, Imperial College, London, UK; Molecular and Population Genetics, Cancer Research UK, London, UK

Abstract

Introduction Progressive loss of cell cycle control is an important feature on the adenoma-carcinoma sequence of colorectal cancer. Cyclin-dependent kinase inhibitor 1A (P21/CDKN1A) is an important target of the TGFβ signalling pathway, and it is commonly under-expressed as colorectal neoplasia develop. The aim of this study was to identify low penetrance germline variation in this gene which predisposes individuals to colorectal cancer.

Methods Variation in the coding region of CDKN1A was determined in fifty colorectal cancer cases with a strong family history and 50 controls were tested using the Lightscanner and direct sequencing. 15 tagging SNPs around CDKN1A were typed in the CORGI cases and controls as part of a genome-wide analysis using the Illumina Hap550 platform in 930 cases and 960 controls performed by colleagues (Tomlinson et al 2007). Allele-specific expression of the gene was examined using quantitative reverse transcriptase PCR linked to SNPs in an upstream promoter region.

Results A novel amino-acid changing variant Phe22Leu was identified in a single colorectal cancer patient. Six patients were identified in the case group and 5 in the control group with Arg31Ser. In the association study the two most significant SNPs lie in an upstream promoter region and are in linkage disequilibrium, both are risk alleles for colorectal cancer (OR 1.13; 95% CI 1.06 to 1.2).

SNP
 
Allele A
Allele b
 p ( χ2)
OR
95% CI
rs4713999
controls
5139
2485
rs4713999
cases
5599
3055
0.000275
1.1284
1.06-1.2
rs10807170
controls
5097
2533
rs10807170
cases
4858
2730
0.000364
1.1308
1.058-1.21
p21 LD inverse p values

p21 LD inverse p values

LD plot p value

There were significant differences in expression between CDKN1A and the controls in 94 samples (p=0.037, Student’s t test), demonstrating linkage of these upstream polymorphisms to allele-specific expression of CDKN1A.

Taqman p21

Conclusion Rare variants of P21/CDKN1A are an infrequent cause of predisposition to colorectal neoplasia. A promoter region upstream of the CDKN1A is associated with prediposition to colorectal neoplasia, and is linked to allele-specific expression of this gene.

 

Autosomal recessively inherited non-polyposis colorectal cancer: genotype and phenotype


Gut 2010;59:A111-A112; doi:10.1136/gut.2009.208983k

Neoplasia and cancer pathogenesis posters
PWE-067 Recessively inherited non-polyposis colorectal cancer: genotype and phenotype

K J Monahan1,2, K Pack2, C Cummings1, H J W Thomas1, I P M Tomlinson2

1 Family Cancer Clinic, Imperial College and St Mark’s Hospital, London, UK
2 Department of Molecular and Population Genetics, Cancer Research UK, London, UK

Introduction: Patients diagnosed before 50 years of age have a likely strong genetic or environmental aetiological factor. There is good evidence from population studies1 that recessive inheritance is common in young colorectal cancer patients.

Methods: A cohort of 133 colorectal cancer patients were diagnosed under the age of 50 years who did not have multiple polyps or a family history suggestive of dominant inheritance. They were identified and recruited from the Bobby Moore Database in the Family Cancer Clinic, St Mark’s Hospital, Harrow. MUTYH was screened for germline mutations. As these patients fulfilled Bethesda criteria they were tested for hereditary non-polyposis colorectal cancer (HNPCC) by microsatellite instability analysis and immunohistochemistry of mismatch repair proteins. Immunohistochemistry was also performed on β-catenin and P53. Loss of heterozygosity of the APC locus at 5q21–22 was tested using a set of microsatellite markers. Sequencing was used to identify somatic mutations in KRAS and BRAF.

Results: Forty-four patients (33%) had cancers proximal to the splenic flexure, 79 (59%) distal and had 11 (8%) synchronous colorectal cancers. Thirty-seven patients (28%) had an affected sibling and 33 (25%) patients had a second-degree relative with cancer at any site. The median age of diagnosis of colorectal cancer was 39 years (range 14–49 years of age). Twenty-six patients (20%) were found to harbour sequence variation in the MUTYH gene but none of these variants were likely to be pathogenic, and there was no difference in the frequency of these compared to a control group of 50 patients. Eighty percent of tumours were found to be microsatellite stable. 20/30 cancers had nuclear localisation of β-catenin and 21/30 had nuclear localisation of P53 antibodies on immunohistochemistry. Loss of heterozygosity of the APC locus at 5q21–22 was present in 14/30 cases. Thus Wnt pathway activation is likely by over half of this group of cancers. Four cancers had BRAF V600E mutations and five had KRAS codon 12 or 13 mutations.

Conclusion: In a cohort of 133 young colorectal cancer patients without multiple polyps, most tumours demonstrated Wnt pathway activation and other somatic changes consistent with the classical adenoma-to-carcinoma sequence. Germline mutations in the colorectal neoplasia predisposition gene MUTYH appear to be rare events in such patients. The majority of recessive inheritance in young patients is probably caused by mutations in unknown predisposition genes.

The Aetiology of Hyperplastic Polyposis Syndrome


THE AETIOLOGY OF HYPERPLASTIC POLYPOSIS SYNDROME IN A LARGE FAMILY FROM THE WEST OF IRELAND

K. J. Monahan1, L. Carvajal-Carmona2, T. Guenther3, T. O’Gorman4, J. Cazier2, I. P. Tomlinson2, H. J. W. Thomas1. 1Family Cancer Clinic, St Mark’s Hospital, 2Molecular and Population Genetics Lab, Cancer Research UK, 3Academic Department of Pathology, St Mark’s Hospital, London, UK, 4Department of Medicine, University College Hospital, Galway, Ireland. Gut 2008;57:A1-A172. BSG 2008.

Introduction: We have identified a family with a dominantly inherited predisposition to mixed histology multiple polyps and colorectal cancer. The family meet WHO criteria for hyperplastic polyposis syndrome. We have attempted to elucidate the gene which predisposes to this condition.

Aims & Methods: Mutations in APC, MYH, SMAD4 and genes which cause HNPCC were excluded by direct sequencing and other methods. Somatic mutations were screened in genes often mutated in colorectal cancers. Genome wide genotypes were obtained for over 10000 SNPs using Affymetrix 10k plus 2 arrays and linkage analysis was performed. Genome wide copy number variation analysis was also performed using the Goldengate SNP platform. Whole genome expression analysis profiles were obtained on cell line RNA using the Affymetrix U133 Plus 2.0 GeneChip oligonucleotide arrays.

Results: The polyps appear to follow a hyperplastic/serrated polyp to mixed serrated/adenomatous (see fig) to adenocarcinoma sequence. Linkage analysis shows a maximum parametric LOD score of 2.71 at 8p22–21.3. Genome wide copy number and loss of heterozygosity (LOH) studies reveal LOH at 8p and 17p in the cancers. A number of genes at that locus including BMP1 and MTUS1 have been screened, the latter gene having more than a fivefold up-regulation in expression.

Conclusion: We have identified a locus on chromosome 8p which predisposes to hyperplastic polyps and colorectal cancer in a large family from the West of Ireland. This is the first time such an association has been identified and may be useful in screening families at risk of colorectal neoplasia.

Related Article: Hyperplastic Polyposis SyndromeTHE AETIOLOGY OF HYPERPLASTIC POLYPOSIS SYNDROME IN A LARGE FAMILY FROM THE WEST OF IRELAND

A dedicated service for the Management of Hereditary Colorectal Cancer Improves Adherence with Molecular Testing for Lynch Syndrome


A DEDICATED SERVICE FOR THE MANAGEMENT OF HEREDITARY COLORECTAL CANCER IMPROVES ADHERENCE WITH MOLECULAR TESTING FOR LYNCH SYNDROME

UEGW Amsterdam 2012

Leon Sergot, Sophie Stevens Poster, Fiona Turkes, Jason Smith, Kevin J. Monahan

The Family History of Bowel Cancer Clinic, West Middlesex University Hospital, London, United Kingdom

INTRODUCTION/OBJECTIVES:

Lynch Syndrome (LS) is responsible for 2-3% of colorectal cancer (CRC) which equates to ~1000 cases of CRC in the United Kingdom annually. Previous studies have demonstrated that in current practise less than 10% of these cases are identified as LS due to lack of appropriate testing. The international Bethesda guidelines were devised in 2002 to help identify such cases for tumour testing for the molecular features of LS, such as immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 expression, or DNA microsatellite instability analysis (MSI). These criteria include all individuals diagnosed

AIMS & METHODS:

We identified all new cases of CRC over 1 year before and after the establishment of a dedicated ‘Family History of Bowel Cancer Service’ in our hospital in March 2011. Adherence to the Bethesda guidelines was determined by examination of medical records and UK National Bowel Cancer Audit Programme (NBOCAP) data. Pathology reports were studied in patients aged 50-59 years at diagnosis for features consistent with MSI-type histology.

RESULTS:

In total, 198 cases of CRC were discussed at the CRC multidisciplinary meeting over a 2 year period. 12 individuals were diagnosed under the age of 50 years (~6%) consistent with Office of National Statistics (ONS) data. 31 patients were diagnosed between 50-59 years, of which 4 patients had MSI-type histology. A further 25 patients had a significant family history of CRC or a LS-related cancer diagnosed under 50 years. Therefore in total 41 patients fulfilled Bethesda criteria (20.7%). Between March 2010-March 2011 there were 18 such cases with only 1 patient’s tumour tested for the molecular features of LS (5.6%) compared to 19/23 cases tested in the subsequent year (82.6%), p value = 9.7e-7 (Chi=23.9956).  Six out of 20 (30%) cases tested demonstrated these molecular features with MSI and abnormal IHC, and are undergoing germline genetic testing.

CONCLUSION:

The establishment of a dedicated family history of bowel cancer service resulted in a significant improvement in testing individuals diagnosed with CRC with a possible diagnosis of LS. We recommend that this service be applied to identify such families throughout the United Kingdom to improve clinical pathways for these patients.

via Abstract View.

Hounslow Chronicle 09/03/2012


 

Giant Inflatable Bowel at West Middlesex University Hospital

http://www.hounslowchronicle.co.uk/west-london-news/health-news/2012/03/01/inflatable-bowel-welcomes-visitors-to-west-mid-109642-30440010/

 

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