TRIPLER ARMY MEDICAL CENTER, Hawaii, USA – Daniel Shockley, a retired Sailor living on Oahu, meets with Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, to discuss recovery and post-operative…
Starting at age 50, it is encouraged that everyone get regular colonoscopies (in the USA), an examination that use a fiber-optic camera to view your lower gastrointestinal tract, to screen for colon cancer.In September 2011 when Daniel Shockley, a retired Sailor living on Oahu, went for his annual physical exam at Spark M. Matsunaga Veterans Affairs Medical Center
, he thought besides a little weight loss, he had a clean bill of health.Since Shockley had just turned 50, he was referred to a Hawaii Pacific Health clinic in downtown Honolulu for his first colonoscopy.
Due to his hectic work schedule, Shockley rescheduled the screening a couple times and it wasn’t until May 8, 2012, when he got the colonoscopy.
“They usually schedule colonoscopies for 1-hour blocks of time, but they found so much wrong during mine that he had to spend a lot of time documenting and taking pictures,” Shockley explained. “What they found was approximately 100 polyps embedded throughout my colon, rectum and anus. And at the traverse colon, the junction between the large and small intestine, they found a large tumor that was creating an 80 percent blockage.”
Shockley was referred to Tripler Army Medical Center’s general surgery clinic, and the week following the screening, he met with Susan Donlon, a certified genetic counselor at Tripler.
Donlon performed DNA tests on Shockley and within three weeks the tests had come back confirming that Shockley has a gene mutation known as Adenomatous Polyposis Coli, which increases a person’s risk of developing colorectal cancer. As a result of the mutation, Shockley was diagnosed with Attenuated Familial Adenomatous Polyposis, a condition in which numerous polyps form mainly in the large intestine.
“I knew surgery was inevitable and I was willing to accept the worst case scenario the whole time,” Shockley said.
On July 13, Shockley underwent a total proctocolectomy with ileostomy surgery, which removed portions of his large intestine to include the entire colon, rectum and anus.
Shockley spent about two weeks in Tripler’s general inpatient surgery ward recovering before he was able to go home. It was nine weeks before he was able to go back to work.
Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, performed Shockley’s surgery and has followed up with him to ensure he is not only well-informed, but also well-educated.
“He knew nothing of his disease and its many facets before we met and our team (at Tripler) began his personal education in order to promote effective counseling regarding his diagnostic and therapeutic options,” Gagliano explained. “Finally we educated him regarding his genetic situation so that he could choose (how to best) inform his family. By giving him great care, we essentially treat an entire family cohort.”
“(Dr. Gagliano and his team) have passion for what they do, and my care was phenomenal,” Shockley expressed. “I cannot say enough good things about my stay and the care they provided.”
Gagliano is very pleased with Shockley’s recovery thus far and attributes it to his attitude.
“I tend not to think about things I can’t control,” Shockley explained. “Medical issues are not something I can control, but what I can control is my attitude and after 51 years on God’s green earth my positive attitude has gotten me this far and I am not going to change it.”
Because of Shockley’s surgeries, he now has an ostomy pouching system, a prosthetic medical device that provides a means for the collection of waste. Nina Lum, certified wound, ostomy and continence nurse, TAMC, who helped care for Shockley throughout his recovery, echoed Gagliano’s remarks.
“Shockley’s resilience in the face of challenges including his tremendous enthusiasm for life, regardless of setbacks, certainly played a huge role in his recovery,” Lum said. “He has always maintained a positive outlook, been fully engaged in his care from the beginning, reached out to the ostomy community not only for support, but also to offer support and advise based on his personal experience.
“He is selfless in trying to reach out to others,” Lum added.
Shockley has embraced his diagnosis and challenged it from the start. He acts as a patient advocate and an ambassador for colon cancer awareness.
“(I want to) share my story with others on behalf of those patients that have gone before me and who were unable to share their story,” Shockley explained. “My catchphrase is ‘AFAP-Seize the disease!'”
Shockley wants to spread the information about his diagnosis and experience so he can inspire others to get the screening and be aware of the condition. Additionally, there is not a lot of information about AFAP available, so he hopes that talking about his diagnosis will help the medical community.
“By maintaining a positive attitude, the opportunity for a success story is much higher,” Shockley said. “This in turn allows me a better chance of overcoming adversities I am faced with during my lifetime.”
Polyposis Syndromes – Information for Patients
Bowel cancer gene discovery cracks mystery of families with a strong history of the disease
Sunday 23 December 2012
Cancer 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.”
Palles, C et al Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas Nature Genetics (2012)
Monday 10 December 2012 – from Cancer Research UK
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.”
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
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.
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.
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.
The study shows that regularly taking the medicine cuts the risk of bowel cancer by more than 60% in those with a particular genetic predisposition to get the disease – as well as reducing the risk of other hereditary cancers.
Scientists who led the study said people with several family members with cancers other than breast, blood and prostate might be advised to start taking aspirin daily from the age of 45.
They said those without a family history of the disease might also consider doing so, but that they should make a personal assessment of the risks and benefits and get medical advice. Anyone thinking of taking the drug regularly should consult their doctor first.
Doctors already prescribe low, daily doses of aspirin to people at increased risk of heart attacks and strokes, and evidence has been growing of anti-cancer properties for 20 years. However, this is the first long-term, randomised controlled trial to show such an effect.
The trial involved people with Lynch syndrome, a genetic abnormality that predisposes carriers to develop bowel cancer and other solid organ cancers including endometrial, ovarian, stomach, kidney, oesophageal, brain and skin tumours.
The condition affects at least one in 1,000 people. Carriers are around 10 times as likely to develop cancer and often do so at a young age.
Professor John Burn of Newcastle University, who led the study, estimated that if all 30,000 or so people with Lynch syndrome in the UK were to start taking two aspirin tablets a day then some 10,000 cancers would be prevented over the next 30 years, saving about a thousand lives. The downside of the treatment is that around an extra thousand people would develop stomach ulcers as a side-effect.
“People with a genetic susceptibility are a model system,” said Burn, whose work is published online in the Lancet on Friday. “They are more sensitive to the environmental triggers to cancer.
“If we can do something to change cancer progression in people at high genetic risk, then that’s telling us what we might all benefit. But we are not making a recommendation for the general population. Everyone can take this evidence and make their own choice.
“In between you have the people who have a family history [of cancer]. Those individuals may well decide to put themselves on aspirin and that would be a reasonable conclusion from the data currently available.”
Between 1999 and 2005, about half of a group of 861 Lynch syndrome carriers were given two aspirins (600mg) a day, while the rest took placebos.
By 2010 those who had taken aspirin for at least two years were 63% less likely to have developed bowel cancer.
Looking at all forms of the disease, almost 30% of those in the placebo group developed a Lynch syndrome-related cancer, compared with 15% for those given aspirin.
The most common side effects associated with taking aspirin are gastrointestinal ulcers and stomach bleeding. There is also an very small increased risk of haemorrhagic stroke, in which a blood vessel in the brain bursts.
There was no difference in the proportions of the study groups suffering such side-effects.
Burn added that he takes low-dose aspirin tablets as a preventative measure. “That was a balanced judgment based on weighing risks and benefits. I know I might get an ulcer or a cerebral bleed but I’d rather not have a heart attack, stroke or cancer. That’s my choice.”
Aspirin is a synthetic version of the active component of willow bark, salicylic acid, which has been used as a medicine for its anti-inflammatory properties for hundreds of years. Salicylates also trigger programmed cell death to help diseased plants contain the spread of infection.
“It’s not a huge stretch to think that if salicylate induces programmed cell death in plants to kill infected cells, maybe it’s doing similar things in the animal kingdom to enhance the death of aberrant cells causing cancer,” said Prof Burn.
“This adds to the growing body of evidence showing the importance of aspirin, and aspirin-like drugs, in the fight against cancer and emphasises how critical it is to carry out long-term international research,” said Prof Chris Paraskeva, a bowel cancer expert at the University of Bristol.
The CAPP team have launched a website to recruit 3,000 people with Lynch syndrome worldwide to take part in a five-year trial to determine the best dose of aspirin to take.
A trial of methotrexate for cancer that has spread in people with a faulty MSH2 gene (MESH)
This trial is looking at the chemotherapy drug methotrexate for people with a MSH2 gene fault who have cancer that started in the bowel, stomach, womb (endometrium), bladder, or lining of the urinary system (urothelium) and has spread.
Every cell contains DNA. This is the genetic information which controls how cells behave. In cancer cells, the DNA is changed or damaged. Cancers can have different types of changes in the DNA. One of these is when a gene called MSH2 is not working properly.
Doctors often use chemotherapy to treat cancer. But sometimes the cancer comes back after treatment and spreads elsewhere in the body.
Methotrexate is a chemotherapy drug that is used to treat some types of cancer. We know from research that methotrexate kills cancer cells when the MSH2 gene is not working properly. Researchers want to find out if it will help people with a faulty MSH2 gene who have cancer that has spread.
The aims of this trial are to
- See how much methotrexate helps people in this situation
- Learn more about the side effects
Who can enter
You can enter this trial if you
- Have cancer that started in your bowel, stomach, womb, bladder or urothelium and has grown into surrounding tissue, or has spread elsewhere in the body
- Have cancer that did not respond to, or has come back after, treatment with standard chemotherapy, or you cannot have standard treatment for some reason
- Have a MSH2 gene fault (the doctors will do tests to confirm this)
- Have satisfactory blood test results
- Are well enough to take part in the trial (performance status 0, 1 or 2)
- Are at least 18 years old
- Are willing to use reliable contraception during the trial and for 6 months afterwards if there is any chance you or your partner could become pregnant
You cannot enter this trial if you
- Have already had treatment with methotrexate unless it was for a non cancerous condition and you finished treatment at least 5 years before you were diagnosed with cancer
- Have had any other cancer in the last 10 years apart from non melanoma skin cancer or carcinoma of the cervix and the trial doctor thinks this could affect you taking part in this trial (If you have Lynch syndrome, you may be able to take part if you have had other cancers – the doctors will advise you on this)
- Have had radiotherapy to a single area of cancer (a lesion) that the researchers will be measuring in this trial, unless the lesion has got bigger since you had radiotherapy
- Have another medical condition that cannot be controlled with medication
- Are pregnant or breastfeeding
This phase 2 trial will recruit 56 people. Everybody taking part will have methotrexate.
You have methotrexate as an injection into a vein. The treatment only takes a few minutes. You have another injection a week later and then 2 weeks without any treatment. Each 3 week period is called a cycle of treatment. You have up to 6 cycles of treatment. But if the treatment is helping you, your doctor may talk to you about having it for longer.
During the trial, the researchers will take samples of blood, urine and a hair follicle (such as from an eyebrow). And they will get a sample of the tissue taken when you had surgery to remove your cancer or when you had a biopsy.
The researchers will use the samples to try to find substances they can measure in the body to help them tell how well the treatment is working. They call these substances biomarkers. And they will use the blood samples to look at your genes. This is to learn more about how genetic changes can lead to cancer and whether certain changes affect how people respond to treatment.
The trial team may also ask your permission to take an extra biopsy during treatment. This is to learn more about what effect the treatment has on the genetic make up of your cancer. If you don’t want to have this extra biopsy, you don’t have to. You can still take part in the trial.
All samples will be stored safely and may be used in the future, but only for research purposes.
You will be asked to fill out a questionnaire before you start treatment, just before the 2nd and 4th cycle of chemotherapy, and every 3 months for a year after you finish treatment. The questionnaire will ask about any side effects you have had and how you have been feeling. This is called a quality of life study.
The trial team will also ask you to fill out a short questionnaire which asks about other members of your family who have had cancer.
People taking part in this trial may also be asked to join extra studies looking at PET scans and MRI scans. Doctors want to find out if these scans can provide more information about bowel cancer with a faulty MSH2 gene.
You may be able to take part in one or both of these studies. Whether or not you are asked to take part will depend on where you are having your treatment and also where in your body the cancer is.
You will see the doctors and have some tests before you start treatment. The tests include
- Physical examination
- Blood tests
- CT scan
- Chest X-ray
- Heart trace (ECG)
You go to hospital twice in each 3 week cycle of treatment. You have regular blood tests. And after 9 weeks of treatment you have a CT scan to check that your cancer has not got any bigger. If the scan shows the cancer has grown, you will stop having the trial treatment and the doctors will discuss other treatment options with you. If the cancer has stayed the same size or got smaller, you will have the next 3 cycles of treatment and then another CT scan.
After you finish treatment you will see the trial doctors and have a CT scan every 3 months for up to 1 year.
If you do take part in the MRI or PET scan study (or both), you will have extra scans
- Before you start treatment
- After 2 weeks of treatment
- When you finish treatment
Having an MRI scan takes about 15 to 30 minutes. If you have PET scans, you have an injection of a small amount of a radioactive drug first. Then you have to wait an hour before having the scan. The scan itself can take up to an hour.
The side effects of methotrexate include
There is more information about the side effects of methotrexate on CancerHelp UK.
Location of trial
For more information
Please note: we cannot help you to join a specific trial. Unless we state otherwise in this trial summary, you need to print this page and take it to your own doctor to discuss.
Find out how to join a trial or contact our cancer information nurses for other questions about cancer by phone (0808 800 4040), by email, or at
The Information Nurses
Cancer Research UK
407 St John Street
Professor David Cunningham
Supported by: Institute of Cancer Research (ICR), The Royal Marsden NHS Foundation Trust
- Lynch Syndrome (familyhistorybowelcancer.wordpress.com)
- Lynch Syndrome and other non-polyposis inherited cancer syndromes (familyhistorybowelcancer.wordpress.com)
The results of one of the biggest efforts yet to understand the complexity and meaning of human genomic data were published last month by the ENCODE (Encyclopedia of DNA Elements) consortium.
This impressive undertaking brings new understanding to the functional aspects of the genome and can probably be considered the most significant genomic discovery step since the sequencing of the whole human genome in 2000. The ENCODE project assigned biochemical function to about 80% of the genome, and in particular to elements outside of the well-studied protein-coding regions.
The findings of the ENCODE consortium – comprising over 400 researchers working in 32 laboratories across the world – indicate that a much greater proportion of the genome is biologically active than had previously been thought, and should effectively dispel the notion of ‘junk’ DNA.
The results of functional analyses on 147 different cell types demonstrate that at least 80% of the genome performs a specific function – mostly regulating the activity of the 2% that comprises protein-encoding genes. The work identified some 4 million regulatory elements in total, many of which are located far away on the genome from the gene they control.
This is arguably the most significant step forward in our understanding of how the human genome works since the releases of the initial draft sequence in 2000 and the final draft in 2003. At that time it was deeply surprising to many to find that humans possessed only around 20,000 genes occupying less than 2% of the genome, leading some to label the other 98% as ‘junk’ DNA.
Evidence from functional and genome-wide association studies over the years has made this an increasingly defunct term as it became apparent that a large proportion of the single base mutations that cause disease fell between gene coding regions, but this new comprehensive analysis should put an end to the idea once and for all.
Dr Ewan Birney of the European Bioinformatics Institute (EBI) in Cambridge who coordinated the data analysis said “This will give researchers a whole new world to explore and ultimately, it’s hoped, will lead to new treatments”. He also pointed out that the job was still far from done, and that deep characterisation is probably only around 10% complete. It is quite possible that much of the remaining 20% of the genome has a functional role that has yet to be identified.
The thirty papers can be freely accessed by all in the journals Nature, Genome Biology and Genome Research.
The mapping provides new insights into gene organisation and most of all, mechanisms of regulation. A central goal in biology – understanding the enormous diversity of gene expression in different cell types under various physiological conditions – can be considered partly achieved.
The project yielded invaluable information on the human transcriptional regulatory network with systematic analyses of transcription factors, chromatin structure and regulatory modifications. All these findings shine new light on our concept of the gene.
Some of the newly identified elements correspond to sequence variants linked to human disease, and can therefore guide interpretation of these variations. Genome-wide association studies have previously identified many noncoding variants associated with common diseases and traits. Such variants systematically perturb transcription, alter chromatin states, and form regulatory networks. ENCODE’s results point to the involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
The publication of such a detailed analysis of the functionalities of the human genome has understandably generated much enthusiasm among scientists and general public alike. Confirmation that a far larger chunk of our genome is biologically active than previously thought has been an exciting discovery and researchers hope the findings will lead to a deeper understanding of numerous diseases.
It is however important to remember, and for the scientific community to clearly acknowledge, that despite these fantastic results it may be many years before patients see any benefits from the project. Better understanding of the functional complexity of the human genome will undeniably lead to improved control of disease and to better treatments, but the road to clinical implications and applications is still long and difficult.
English: View of ENCODE project tracks in the UCSC Genome browser (Photo credit: Wikipedia)
Research published in the journal Gastroenterology has found that fewer than 10% of bowel cancer patients who are at high risk of having Lynch Syndrome are appropriately screened for the condition in the United Kingdom.
Lynch Syndrome is an inherited genetic disorder which affects the genes responsible for detecting and repairing damage in the DNA, around half of whom develop cancer, mainly in the bowel and womb. Lynch Syndrome causes around 3% of bowel cancer cases in the UK.
When several members of the same family are diagnosed with bowel cancer it is recommended that they are screened for Lynch Syndrome.
Researchers investigated the clinical pathways of 554 bowel cancer patients in two UK hospitals. They found that fewer than 10% of bowel cancer patients who were at high risk of Lynch Syndrome were appropriately screened for the condition.
For the abstract as presented at Digestive Diseases Week, San Diego May 2012 click here.
- Lynch Syndrome (familyhistorybowelcancer.wordpress.com)
- Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit (familyhistorybowelcancer.wordpress.com)
Background Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.
Methods We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan–Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period–specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
Results Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
Conclusion Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
Risks of Primary Extracolonic Cancers Following Colorectal Cancer in Lynch Syndrome
Cumulative risks (percent) and corresponding 95% confidence intervals (CIs) of primary extracolonic cancers during the 10 and 20 years following diagnosis of colorectal cancer for carriers of mismatch repair gene mutations
||(0.87 to 3.17)
||(2.86 to 7.68)
| Urinary bladder
||(0.65 to 2.75)
||(1.37 to 5.20)
| Small intestine
||(0.28 to 1.73)
||(1.92 to 6.41)
||(0.13 to 1.40)
||(0.19 to 2.48)
| Hepatobiliary tract†
||(0.16 to 1.69)
||(0.42 to 2.73)
||(0.86 to 4.77)
||(2.69 to 9.76)
||(7.66 to 17.11)
||(16.79 to 32.84)
||(0.58 to 3.83)
||(0.63 to 16.69)
||(0.00 to 2.11)
||(0.50 to 4.14)
* Kidney etc. included kidney, renal pelvis, ureter and other and unspecified urinary organs.
† Hepatobiliary tract included liver and intrahepatic bile duct, gall bladder, and other and unspecified parts of biliary tract.
Patients who have had colorectal cancer and who are carriers of the DNA mismatch repair gene mutations that cause Lynch syndrome “have an increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers,” according to a study in the Journal of the National Cancer Institute.
Previous studies had shown that mutation carriers “are at a substantially increased risk of cancers of the colon, rectum, endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel, hepatobiliary tract, and pancreas,” the authors noted. A major inherited cancer syndrome, Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC).
The study was based on data for 764 patients from the Colon Cancer Family Registry, evenly divided between men and women, who were carriers of the mismatch repair gene mutation and previously diagnosed with colorectal cancer. Most of the carriers (52%) were recruited in Australia and New Zealand, with 33% from the United States and 15% from Canada. The average age at diagnosis of colorectal cancer was 44 years.
Compared with the general population, following colorectal cancer, carriers of mismatch repair gene mutations had a 70-fold increased risk for cancer of the small intestine, a 13-fold increased risk for cancer of the kidney, renal pelvis, and ureter or urethra, a 7-fold increased risk for cancer of the bladder, a 6-fold increased risk for hepatobiliary tract cancer, and a nearly 6-fold increased risk for gastric cancer. Men had a 2-fold increased risk of prostate cancer. The most common primary cancer following colorectal cancer for women with Lynch syndrome was endometrial cancer, with a 40-fold increased risk compared to the general population. There were 20 breast cancers and 6 ovarian cancers in the study population.
“These new data provide further determination of cancer risks, potentially informing and justifying ongoing studies to create the evidence for effective screening methodologies and intervals in [mismatch repair] gene mutation carriers,” the researchers concluded. “Larger studies are needed to refine risk estimates separately for specific [mismatch repair] gene mutations to best inform policies on clinical risk management.” ■
Lynch Syndrome / Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes
Lynch Syndrome (also known as Hereditary non-polyposis colorectal cancer(HNPCC; OMIM 120435)) accounts for approximately 2.2-4% of all colorectal cancer (Hampel et al. 2005). Lynch Syndrome is a familial cancer syndrome which accounts for approximately 2-3% of all colorectal cancer in the UK. It has formerly been known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.
An Irish family tree with Lynch Syndrome caused by an inherited mutation in MSH2. Members of this family are affected predominantly with colorectal cancer (CRC), but also small bowel cancer (SBCa), Gastric, Pancreatic, Uterine and other cancers, as well as conditions not linked to Lynch Syndrome such as Crohn’s disease.
LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. A minority of these families may be identified because they have multiple affected members diagnosed at an early age. The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening. Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers. The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies. Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.
Immunohistochemistry and microsatellite instability analysis for Lynch Syndrome
Amsterdam I Criteria
- ≥3 1st degree relatives with colorectal cancer (CRC)
- ≥2 generations affected
- One family member below age 50 years of age
- Exclude familial adenomatous polyposis
Amsterdam II Criteria
- As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter.
Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS . For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours. If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.
The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising various screening tools combined with genetic and immunohistochemical tests. Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair). If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.
Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines. Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data . A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.
Bethesda (revised) Criteria (Umar et al 2003)
- 1 CRC below age 50 yr
- Multiple CRC or HNPCC-related cancers
- CRC with MSI-related histology under 60 years of age
- CRC or HNPCC-related cancer in ≥1 1st degree relative, < 50 years of age
- CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age
MSI-type Histology: Using the revised Bethesda Criteria patients aged 50-60 years should have tumour testing
There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome. It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer. The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000). The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).
Screening tumours for Lynch Syndrome – is it cost effective?
There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.
In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.
In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).
Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.
These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations
Large bowel surveillance for Lynch syndrome family members and gene carriers
Total colonic surveillance (at least biennial) should commence at age 25 years. Surveillance colonoscopy every 18 months may be appropriate because of the occurrence of interval cancers in some series. Surveillance should continue to age 70–75 years or until co-morbidity makes it clinically inappropriate. If a causative mutation is identified in a relative and the consultand is a non-carrier, surveillance should cease and measures to counter general population risk should be applied.
The effectiveness of colonoscopic surveillance for people with MMR gene mutations and Lynch family members has been examined in retrospective case–control comparisons. Screened individuals were compared to control subjects who declined, or did not receive, regular colonoscopy with respect to outcomes of cancer incidence, tumour stage and mortality, or mortality alone. Surveillance appears to provide an average of 7 years of extra life for Lynch syndrome family members. Thus, available evidence supports regular colonoscopic surveillance as a means of early colorectal cancer detection, leading to mortality reduction as well as reduction in cancer incidence.
Surveillance should consist of total colonoscopy, since the risk of polyps and cancer is high and a substantial proportion of patients have neoplasia restricted to the proximal colon. Colonoscopy is preferable to flexible sigmoidoscopy combined with barium enema. Because the cancer risk is high, it is not appropriate to accept an incomplete colonoscopy until the next surveillance interval. Incomplete colonoscopy should be followed soon after, or even the same day, by completion CT colonography in centres skilled in providing this technique to a high quality, but repeated radiation exposure should be avoided wherever possible. Repeat full colonoscopy or barium enema remain as options. Chromoendoscopy and narrow wavelength visible light (narrow band) endoscopy may have a place in the detection of small or flat lesions, but there is very limited experience and evidence is restricted to descriptive studies of their use in Lynch syndrome surveillance. Hence, the utility of such techniques requires further assessment and is neither recommended nor discouraged in high risk surveillance, but should not replace conventional endoscopic approaches. Evidence for commencing surveillance at 25 years of age is based on observational data that indicate that the risk increases substantially from age 25 in groups defined by family history and in groups defined by presence of a mutation.
Colorectal resection has a place as prophylaxis and for established cancer in Lynch syndrome family members and/or MMR gene carriers.
Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure that includes both a cancer control element and prophylaxis to counter future cancer risk. At present there is no evidence to guide decision-making on primary prophylactic surgery for patients who do not yet have cancer.
People with MMR gene mutations or those from Amsterdam positive Lynch syndrome families who have cancer will require surgery unless treatment is palliative. Case series evidence shows that the risk of metachronous colorectal cancer is high following segmental resection (16%), but substantially lower after colectomy and ileorectal anastomosis (3%). Hence, incorporating a prophylactic element to the cancer resection is appropriate. For patients with proximal tumours, colectomy and ileorectal anastomosis is most relevant, but the retained rectum must be screened because cancer risk in the retained rectum is 3% every 3 years for the first 12 years.
Upper gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers
In families manifesting gastric cancer as part of the phenotype, biennial upper gastrointestinal endoscopy should be considered. The evidence is limited and a pragmatic recommendation is to screen from age 50 since the incidence is very low until that age. Surveillance should continue to age 75 or until the causative mutation in that family has been excluded. This recommendation is based on observations that some Lynch syndrome families have a particular propensity for gastric cancer. There is as yet no evidence that this reduces mortality.
Other non-polyposis predisposition to colorectal neoplasia
About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes. Often they are acquired sporadic type cancers caused by methylation of MLH1. These associated with a particular genetic pathway which differs from HNPCC by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005). Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).
In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006). These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age. The genetic aetiology is not known for these families.
Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis. The genetic risk is partially made up by inherited mutations which cause HNPCC. However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.