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From snapshot to family tree – writing the evolutionary rule book of cancer


HomeFor 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.

To read more from this article which features in the Cancer Research UK Science blog, click here

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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.

New bowel screening test introduced in England


Cancer Research UKNew bowel screening test introduced in England

A new addition to the bowel screening programme is being rolled out

Back in December we wrote about Jeremy Hunt’s announcement that six centres in England would start using Bowel Scope Screening (BSS, also known as flexi-scope or flexible sigmoidoscopy) as part of their bowel screening programme in 2013.

This week, 55 year olds in the South of Tyne region (which includes Gateshead, Sunderland and South Tyneside) received the first wave of letters inviting them to be screened.

This is great news. Cancer Research UK has been involved in Bowel Scope Screening from the beginning – we co-funded a 16 year study  which showed that it cuts deaths by over 40 per cent, and – unlike the current test – can actually prevent a third of bowel cancers among those screened.

As a result, it has the potential to save thousands of lives from bowel cancer each year.

As soon as the trial results were published in 2010, we said we wanted the Government to add BSS to the existing bowel screening programme, and later that year, they agreed, setting aside £60m to fund it.

Since then we’ve been calling for Bowel Scope Screening to start as soon as possible, so it’s fantastic to see it finally happen.

What does the test do?

The test used in Bowel Scope Screening, flexible sigmoidoscopy , uses a flexible tube with a camera and a light on the end to look into your lower bowel. It can spot both early-stage cancers and pre-cancerous growths known as ‘polyps,’ which can be immediately removed to prevent them developing into cancer.

There’s information about having sigmoidoscopy on our website, or you can watch this video.

Recent studies have shown that people find it ‘acceptable’ and ‘reassuring’.

It’s not a new test – it’s been used to diagnose bowel cancer in patients with symptoms for many years. But what is new is using it in this way to screen the population before they even have symptoms. And this could have a huge impact on bowel cancer in this country.

When will it be available?

This is the first of six ‘pilot’ centres which will iron out any potential problems in the system before rolling out BSS to the rest of the country. Over the next few months, another five centres will then start to offer Bowel Scope Screening.

By 2016, everyone in England should be invited to have a test at the age of 55.

What does it mean for me?

Bowel Scope Screening adds to the  existing bowel screening programme, which uses the Faecal Occult Blood Test (FOBT) – which looks for blood in your stools. People are invited from age 60 to participate (or age 50 in Scotland).

Under the new plans, if you live in England, you’ll be invited to be screened using BSS when you turn 55. If you decide not to go (and it is your decision), you can change your mind up until you turn 60. At that point you’ll be invited to take part in the existing bowel screening programme.

Whether or not you decide to have BSS, you will still be invited to take part in the existing screening programme at 60, to help spot any cancer that might develop later on. Although it hasn’t been shown to prevent cancer in the same way as BSS, FOBT is still an important way of helping to diagnose bowel cancer at an early stage, when treatment is more likely to be successful. The evidence so far suggests it’s made a big impact already and BSS takes this a step further.

What’s next?

This is an important first step. Now we need to make sure that everyone can benefit from Bowel Scope Screening. At the moment BSS is only being rolled out in England. We want to see Scotland, Wales and Northern Ireland develop their own plans for BSS, including making sure they have the right facilities available.

If this test is made available across the UK, thousands of deaths will be prevented, and – even better – potentially thousands of people will be spared from ever having to experience this terrible disease.

 

Family history of bowel cancer increases odds of survival


CRUK LogoFamily history of bowel cancer increases odds of survival

Wednesday 20 March 2013

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.”

 

Bowel cancer gene discovery cracks mystery of families with a strong history of the disease


Bowel cancer gene discovery cracks mystery of families with a strong history of the disease

Sunday 23 December 2012

Cancer Research UK Press Release

Scientist using microscopeCancer Research UK-funded scientists have discovered that two gene faults increase the risk of bowel cancer in families with a strong history of developing the disease, who, until now, had no explanation as to why their risk was greater. The research is published in Nature Genetics1.

To find the faults, the researchers from the University of Oxford and The Institute of Cancer Research, London, scanned the genes of 20 people2 from families with a strong history of bowel cancer. They found everyone who had a faulty POLE or POLD1 gene developed bowel cancer or had a precancerous growth in the bowel.

The two genes are so-called ‘dominant’ genes, where only one faulty copy needs to be inherited for someone to be at a high risk of developing bowel cancer.

To confirm their findings they then looked for the faults in almost 4,000 people with bowel cancer and 6,700 without the disease. Neither of the faults were found in people without bowel cancer, while 12 people with the POLE gene were found in the bowel cancer group and one person had a POLD1 gene fault.

The POLD1 fault was also found to increase the risk of getting womb cancer and possibly brain tumours with seven people in the study being diagnosed with womb cancer and one developing two brain tumours.

Cancer Research UK’s Professor Ian Tomlinson, lead researcher based at the University of Oxford, said: “There are some families where large numbers of relatives develop bowel cancer but who don’t have any of the known gene faults that raise the risk of developing the disease.

“These two faults are rare, but if you inherit them your chance of bowel cancer is high. By testing people with a strong family history of the disease for these faults, we can identify those who are at high risk and try to prevent the disease by using colonoscopy and other methods.”

POLE and POLD1 are involved in scanning and repairing damage to DNA, removing incorrect sequences from the DNA chain. Without these genes, affected individuals build up damage in their DNA which can cause bowel cancer.

Study co-leader Professor Richard Houlston from The Institute of Cancer Research said: “Uncovering gene faults like these two is extremely important, as inherited susceptibility plays a role in the development of about a third of all cases of colorectal cancer.

“This is one of the most important discoveries in bowel cancer genetics in years. It should allow us to manage families affected by inherited bowel cancer much more effectively, and it offers new clues for the prevention or treatment of all forms of the disease.”

Joe Wiegand, a financial advisor from Hampshire, was diagnosed with bowel cancer seven and a half years ago at just 28 years old. Joe had most of his large bowel removed and six months of chemotherapy. His treatment was successful and he is now followed up once a year with a sigmoidoscopy. As many of Joe’s relatives had also had bowel cancer, during his treatment he was invited to take part in this study to investigate genetic faults that may be behind his cancer.

Joe said: “There’s a very strong history of bowel cancer in my family – my dad’s mother and sister both had it, my dad was diagnosed with it at 43 and a few cousins have had bowel cancers and brain tumours. It’s clear that something’s going on in our family. I hope that taking part in this study will spare my two children the uncertainty of not knowing if they have this gene fault by having a simple yes or no blood test.”

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This research provides another piece of the puzzle for families who have a much greater risk of developing bowel cancer.

“Cancer Research UK scientists have played an important role in finding the gene faults that increase cancer risk. Their work means doctors can help families with a strong family history by preventing cancer from developing or diagnosing it earlier to help more people survive.”

Reference

Palles, C et al Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas Nature Genetics (2012)

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.

 

UK Sequencing project will map DNA of up to 100,000 patients


 

CRUK LogoSequencing project will map DNA of up to 100,000 patients

 

Monday 10 December 2012 – from Cancer Research UK

The genetic data could help researchers develop drugs and tests which could help save thousands of lives

A new £100m project will map the DNA of up to 100,000 patients with cancer and other rare diseases.

The large-scale mapping initiative will take place in England over the next three to five years and is intended to lay the foundations for a revolution in NHS treatment.

The genetic data will help researchers to develop new drugs and tests that could help save thousands of lives.

Britain should “push the boundaries” and become the first country to introduce genetic sequencing to its mainstream health service, according to the prime minister David Cameron.

He said: “Britain has often led the world in scientific breakthroughs and medical innovations, from the first CT scan and test-tube baby through to decoding DNA. By unlocking the power of DNA data, the NHS will lead the global race for better tests, better drugs and above all better care.We are turning an important scientific breakthrough into a potentially life-saving reality for NHS patients across the country.”

He added: “If we get this right, we could transform how we diagnose and treat our most complex diseases not only here but across the world, while enabling our best scientists to discover the next wonder drug or breakthrough technology.”

Dr Harpal Kumar, Cancer Research UK’s chief executive, welcomed the plans: “This work will uncover a wealth of new information which doctors and scientists will use to learn more about the biology of the disease and to develop new ways to prevent, diagnose and effectively treat cancer.

“We’re very excited about personalised medicine – some targeted treatments, such as imatinib, a drug for chronic myeloid leukaemia are already helping to treat patients more effectively – and we’re working hard, with many others – to develop new treatments, and to ensure the NHS can effectively deliver a more personalised cancer treatment service.”

He added: “We hope that this vital investment, together with other measures, such as continued support to diagnose cancers earlier, when treatment is more likely to be successful, will be an important step towards saving more lives from cancer, sooner.

“But, it will be some time before everyone with the disease will be able to have treatment based on the genetic make-up of their cancer.”

The NHS already analyses single genes in cancer tests to determine the chances of particular patients having side-effects from treatment.

Professor Dame Sally Davies, the government’s chief medical officer, explained: “At the moment, these tests focus on diseases caused by changes in a single gene.

“This funding opens up the possibility of being able to look at the three billion DNA pieces in each of us so we can get a greater understanding of the complex relationship between our genes and lifestyle.”

The £100m earmarked from the project, which stems from existing NHS budgets, will be spent on training genetic scientists, mapping patients’s DNA, and creating systems for handling the information.

The Human Genome Project, which made an initial ‘rough draft’ of the human genetic sequence in 2011, cost approximately £500m.

But technological advances have cut costs dramatically, meaning the procedure can now be performed for under £1,000 per person, and officials believe the new £100m DNA mapping investment could reduce prices further still.

All patients will be asked for permission before their DNA is sequenced, with all subsequent data anonymised before it is stored.

Alongside the DNA mapping announcement, the government also allocated £100m of new science funding in the Autumn Statement to the life sciences sector.

The money will help build research capabilities for synthetic biology, facilities for manufacturing cell and biological medicines such as antibodies and vaccines.

Science minister David Willetts said: “Life sciences is one of the most truly international sectors – so if we are to continue to be a world player and compete in the global race we must do everything we can to support it.

“In the past year, our initiatives have attracted more than £1 billion of private sector investment to the UK. We can see clear evidence the UK is succeeding in creating the right environment to attract global investment to our shores and continue to be world leader in life sciences.”

 

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

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