This article provides a historical overview of the online database (www.insight-group.org/mutations) maintained by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.
The InSiGHT colorectal cancer hereditary mutation database can be found here
Don’t be embarrassed to go to your GP .
A consultant at West Middlesex University Hospital is urging people to go to their GP if they have symptoms linked to bowel cancer. Dr Kevin Monahan, Consultant Gastroenterologist, runs the Family History of Bowel Cancer Clinic at West Middlesex, and is speaking out to support bowel cancer awareness month during April. He says: “If for the last three weeks you’ve had blood in your poo or it’s been looser, go and see your GP. “We know that people are reluctant to visit their GP if they experience symptoms because they’re embarrassed and worried about wasting the doctor’s time. “But it could save your life. Over 90 per cent of bowel cancer patients diagnosed with the earliest stage of the disease survive five years from diagnosis compared with only 6.6 per cent of those diagnosed with advanced disease. “Bowel cancer is the third most common cancer in the UK for men and the second most common cancer for women. Every year more than 30,000 people will develop it. An estimated 13,000 people die annually from bowel cancer. “Many people worry about getting bowel cancer, sometimes because a relative has had it. At West Middlesex I run a Family History of Bowel Cancer Clinic specifically for those people who may be at higher risk of developing the disease. “The cause of most bowel cancers is not known, but we do know that some risk factors can increase your chances of developing cancer. This includes having one close relative aged under 50 or at least two close relatives on the same side of the family who developed bowel cancer at any age. “If these apply to your family and you’re worried about your risk of developing bowel cancer, you may want to talk to your GP. If your GP thinks there’s a chance you may have an increased risk of developing bowel cancer because of your family history, they can refer you to the Family History of Bowel Cancer Clinic here or elsewhere for advice and treatment.”
Making Universal Screening for a Reality: The Lynch Syndrome Screening Network
March 22nd, 2012 11:35 am ET – From CDC
Deb Duquette, MS, CGC, Sarah Mange, MPH- Michigan Department of Community Health, Cecelia Bellcross, PhD, MS- Emory University, Heather Hampel, MS, CGC- The Ohio State University, Kory Jasperson, MS, CGC- Huntsman Cancer Institute
Authors are all from the Lynch Syndrome Screening Network (LSSN) Founding Board of Directors
flow chart individualEvery day, about 400 people in the United States are diagnosed with colorectal cancerExternal Web Site Icon. Approximately twelve of them have Lynch syndrome, a hereditary condition that increases the risk of colorectal cancer and other cancers. Identifying people with Lynch syndrome could have substantial health benefits for them, their families, and communitiesExternal Web Site Icon.
Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancer; it also leads to increased risks of ovarian, pancreatic, and several other cancers, which often occur at a younger than average age. Lynch syndrome occurs among men and women in all ethnic groups in the United States. A diagnosis of Lynch syndrome offers an opportunity to 1) enhance cancer prevention and screening measures for patients and families, 2) prevent cancer or detect it earlier, and 3) save lives and is cost-effectiveExternal Web Site Icon.
In 2009, the Evaluation of Genomic Applications in Practice and Prevention Working Group published an evidence-based recommendationExternal Web Site Icon that every person newly diagnosed colorectal cancer should be offered screening for Lynch syndrome to identify opportunities to reduce morbidity and mortality in their relatives.
Lynch syndrome screening is performed by analyzing tissue from the person with colorectal cancer for specific pathologic features. If the results suggest the possibility of Lynch syndrome, the affected person is offered genetic counseling and additional testing. Offering screening to all newly diagnosed colorectal cancer patients—regardless of age, ethnicity or family history—is termed “universal screening.” This approach supports an objective of Healthy People 2020, which is to:
‘Increase the number of newly diagnosed colorectal cancer patients who are screened for Lynch syndromeExternal Web Site Icon’
In September 2011, a group of 37 dedicated people from leading cancer institutions created the Lynch Syndrome Screening Network (LSSN)External Web Site Icon, with the goal of reducing the cancer burden associated with Lynch syndrome. LSSN has already received more than 80 institutional applications for membership. More than half of the applicant institutions have already implemented universal Lynch syndrome screening and the others are either interested or in the process. The LSSN will facilitate implementation of universal Lynch syndrome screening by promoting sharing of resources, protocols, and data. LSSN Founding members have already gathered existing educational resources and created a new database to monitor progress toward achieving the Healthy People 2020 objective for Lynch syndrome.
Each first-degree relative (parent, sibling, or child) of a person with Lynch syndrome has a 50% risk of carrying the gene mutation and should be offered genetic counseling and testing. Relatives of a person with Lynch syndrome who are not found to have the gene mutation for Lynch syndrome will typically have the same risk for colorectal cancer as the general population, and their children will not be at risk for Lynch syndrome. Family members who are found to have the gene mutation for Lynch syndrome can be offered earlier and more frequent screening for colorectal and other cancers. Because these people can pass the gene mutation on to their children, the children should also be offered testing after reaching adulthood.
Genetic testing in family members of persons with a Lynch syndrome gene mutation is called “cascade testing.” Cascade testing will allow the Healthy People 2020 objective to achieve population health impact by preventing additional cancers in family members.
March is National Colorectal Cancer Awareness month. This month, increasing awareness of Lynch syndrome is especially timely, as the importance of collecting and sharing information regarding family history of colorectal cancer is being promoted throughout the United States (Colon Cancer AllianceExternal Web Site Icon ; Family PLZExternal Web Site Icon). People with an immediate family member diagnosed with colorectal cancer should share this information with their health care providers, so that screening for Lynch syndrome can be considered.
Lynch Syndrome International is promoting March 22, 2012, as LYNCH SYNDROME PUBLIC AWARENESS DAY. To learn more, please visit Lynch Syndrome International Home pageExternal Web Site Icon ( or the Lynch Syndrome Hereditary Cancers Public Awareness pageExternal Web Site Icon or LSI on FacebookExternal Web Site Icon)
We have launched our ‘Never Too young’ campaign to raise awareness of bowel cancer in patients under the age of 50. Every year 2,100 younger people are diagnosed with bowel cancer in the UK, of which 21 are in their teens. Currently too many are being diagnosed late when treatment is harder and too many lives are needlessly being lost from this treatable disease.
March 22nd is Lynch Syndrome Hereditary Cancer Day. We urge every institution to acknowledge this day with some activity involving public education, public awareness or medical provider training. Together, we can make a difference.
NCHPEG and the American Medical Association (AMA) have released a free Web-based educational program designed to improve the primary care provider’s ability to identify hereditary colorectal cancer syndromes in their patients. This program focuses on case-based learning through a series of clinical scenarios that apply point-of-care tools to key clinical roles in risk assessment, genetic testing, communication, and management. The program also provides access to the point-of-care tools as downloadable pdfs for use in patient care.
“With rapidly developing advances in genetic and molecular medicine, physicians are seeking ways to stay up-to-date in this field to better serve their patients,” said AMA President Jeremy A. Lazarus, M.D. “These developments have made it possible for physicians to now identify hereditary cancer syndromes by looking for specific clues in a patient’s personal and family medical history. We created this educational program to help physicians identify, evaluate, communicate with and manage patients at increased risk for colorectal cancer.”
Colorectal cancer affects approximately 140,000 individuals annually in the U.S. Like other cancers, it develops due to a combination of genetic, biologic and environmental factors interacting together. Approximately 5-10 percent of colorectal cancers are caused by a hereditary syndrome in which a single gene alteration conveys a high risk of colorectal and sometimes other cancers. Individuals suspected to have a hereditary cancer syndrome can sometimes be offered genetic testing to aid in the diagnosis.
“Physicians and other health providers often need information and tools to integrate genetics into their practice,” said NCHPEG Executive Director Joan Scott, M.S., C.G.C. “We developed this program to allow providers to learn as they apply skills through working through cases. They leave the program with knowledge, skills and easily accessible point-of-care tools they can use with their patients.”
This course is available freely available to all users. CME is available in both an enduring, traditional format and a performance improvement format. The enduring format of the course has been certified for 6.0 AMA PRA Category 1 CreditsTM, while participants who complete all three stages of the performance improvement format are eligible for 20.0 AMA PRA Category 1 CreditsTM.
This program was funded by Myriad Genetics, VHA Contract #VA200P0034, AMA, and Humana.
Interested in taking the program? The course is available in both an enduring format and a performance improvement format for CME credit. Individuals who do not plan to apply for CME should register for the enduring course. Click on the links to read more about each option and register.
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.
Read the original paper here (Aune et al British Medical Journal 2011)
Data sources PubMed and several other databases up to December 2010 and the reference lists of studies included in the analysis as well as those listed in published meta-analyses.
Results 25 prospective studies were included in the analysis. The summary relative risk of developing colorectal cancer for 10 g daily of total dietary fibre (16 studies) was 0.90 (95% confidence interval 0.86 to 0.94, I2=0%), for fruit fibre (n=9) was 0.93 (0.82 to 1.05, I2=23%), for vegetable fibre (n=9) was 0.98 (0.91 to 1.06, I2=0%), for legume fibre (n=4) was 0.62 (0.27 to 1.42, I2=58%), and for cereal fibre (n=8) was 0.90 (0.83 to 0.97, I2=0%). The summary relative risk for an increment of three servings daily of whole grains (n=6) was 0.83 (0.78 to 0.89, I2=18%).
Conclusion A high intake of dietary fibre, in particular cereal fibre and whole grains, was associated with a reduced risk of colorectal cancer. Further studies should report more detailed results, including those for subtypes of fibre and be stratified by other risk factors to rule out residual confounding. Further assessment of the impact of measurement errors on the risk estimates is also warranted.
Figure: Dose-response analyses between dietary fibre and risk of colorectal cancer. NHS=Nurses’ Health Study; HPFS=Health Professionals Follow-up Study
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.
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
|Cancer site||10 years||20 years|
|Risk, %||(95% CI)||Risk,%||(95% CI)|
|(0.87 to 3.17)||5.15||(2.86 to 7.68)|
|Urinary bladder||1.61||(0.65 to 2.75)||3.15||(1.37 to 5.20)|
|Small intestine||0.92||(0.28 to 1.73)||4.00||(1.92 to 6.41)|
|Stomach||0.66||(0.13 to 1.40)||1.15||(0.19 to 2.48)|
|Hepatobiliary tract†||0.83||(0.16 to 1.69)||1.42||(0.42 to 2.73)|
|Prostate||2.74||(0.86 to 4.77)||5.90||(2.69 to 9.76)|
|Endometrium||12.12||(7.66 to 17.11)||23.99||(16.79 to 32.84)|
|Breast||1.94||(0.58 to 3.83)||11.38||(0.63 to 16.69)|
|Ovary||0.94||(0.00 to 2.11)||2.08||(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.” ■
If there’s one thing most of us don’t like talking about, it’s our bowel movements. However, your stools (that’s poo to you and me) can be a clear indicator of how healthy your insides are, particularly problems with your digestive system. Many of us are too embarrassed to talk about discomfort of going to the toilet. But even short-term problems can indicate longer-term health risks that can go undiagnosed if you don’t do anything about them.
The Food Hospital Fibre Challenge aims to tackle the toilet taboo and encourage people to make simple changes in their diet that could have significant benefits to their bowel and overall health.
Find out more about our approach.
Take the Fibre Challenge
The Fibre Challenge has been devised by specialist dietitians and is a mass participation initiative to assess the effect of fibre on the nation’s bowel health. For 21 days, you’ll eat extra dietary fibre and send information about your bowel movements (anonymously) to our expert team for analysis. The results will help us to better understand whether a high fibre diet significantly improves short-term bowel health and general well-being. There are some people who shouldn’t take part for health reasons, but the rest of you can download the app, check out the assortment of fibre foods to add to your diet, print-out our stool chart and monitor the effects of eating extra fibre over the next few weeks. Find out more about the challenge.