Genetic testing

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Controversial 23andMe DNA test comes to UK

indexA personal DNA test that has sparked controversy in the US has been approved for use in the UK by regulators.

The Medicines and Healthcare Products Regulatory Agency (MHRA) says the 23andMe spit test, which is designed to give details about a person’s health risks based on their DNA, can be used with caution.

But critics say it may not be accurate enough to base health decisions on.

The company, California-based 23andMe, stands by its test.

Backed by Google, the firm offered US customers details of health risks based on gene variants they carry.

But in November 2013, the US Food and Drug Administration (FDA) banned the company from marketing its service in the US, claiming 23andMe had failed to provide adequate information to support the claims it made about results.

A month later, the company stopped offering genetic tests related to health.

‘Think carefully’

An MHRA spokesperson said it regulated such tests in the UK to make sure they met minimum standards.

23andMe’s mission is to ensure that individuals can personally access, understand and benefit from the human genome”

Anne Wojcicki Chief executive, 23andMe

“People who use these products should ensure that they are CE marked and remember that no test is 100% reliable so think carefully before using personal genome services.

“If after using the service, you have any questions or concerns you should speak to your healthcare professional.”

She added: “If you are concerned that you have an incorrect result due to a faulty product, you can report this to MHRA at or 020 3080 7080.”

The UK Department of Health said it was behind the idea of using gene tests to guide patient care within the NHS, but echoed the MHRA advice on giving careful consideration before opting for services like the one offered by 23andMe.

23andMe chief executive Anne Wojcicki said: “The UK is a world leader in genomics and we are very excited to offer a product specifically for UK customers.”

Ms Wojcicki is separated from but still legally married to Sergey Brin, the co-founder of Google – which has invested millions in 23andMe.

The company had previously offered results on a customer’s risk for 254 diseases and conditions, including identifying genes linked to heart disease and breast cancer. There was also information on how individuals might respond to certain medicines.

Genetic testing is an important medical tool in certain situations, but for healthy people as a way to predict common complex diseases, it’s pretty useless”

Dr Marcy Darnovsky Center for Genetics and Society

But the FDA said the reliability of such tests had not been proven to its satisfaction. It was also worried that some customers could make life-changing decisions based solely on their results.

The UK Department of Health said the product launched in Britain was very different to the service halted by the US regulator.

“Many of the drug responses, inherited conditions and genetic health risks that were of concern in the US have been removed,” a spokesperson told BBC News.

In October, 23andMe said it would sell kits in Canada – these too contain only a handful of health-related results.

“I think a large part of it is trying to expand their markets,” said Professor Hank Greely, director of the Center for Law and the Biosciences at Stanford University in California.

“They may also want to make it clear to the public, to their investors, to their employees that they’re alive and kicking.”


‘Understandable concern that this type of genetic testing’

23andMe said it does not share the genetic data with insurance companies or any other interested party without a person’s explicit consent.

“The science is soundest behind 23andMe’s ancestry reports, which are good, but the majority of the rest of the reports are generally based on very small shifts of risk, which are better served by simply living healthier and getting more exercise,” said Dr Ewan Birney – associate director of the EMBL-European Bioinformatics Institute in Cambridge and unconnected with 23andMe, although he has used one of its kits.

“Despite 23andMe’s careful use of language and explanation, there is an understandable concern that this type of genetic testing could cause inappropriate harm simply through people worrying excessively or becoming neurotic over these small increases in risk.”

In the UK, 23andMe is not the first to launch genetic testing. The NHS’s 100,000 genome project conducts full genome sequencing as opposed to genotyping, whichcompares common differences in known genes. The NHS’s project, which is set to complete its pilot stage by 2017 as part of analysing how best to use genomic data in health care, is “world leading”, said Birney.

“This government is developing the use of genomics for patient care within the NHS,” a Department of Health spokesperson said. “We welcome initiatives that help to raise awareness of genomics and those which enable people to take more interest in their personal health but we urge people to think carefully before using private genomic services as no test is 100per cent reliable.”

“For the curious and the scientists, 23andMe is fine, it’s fun and you can have a ball with your ancestry, but for the general population the NHS is truly working out how best to use this in a way that is world leading,” said Birney. “If you’re waiting for the technology to catch up with you, the NHS will deliver.”



What’s the plan?

Dr Marcy Darnovsky, executive director of the Center for Genetics and Society in California, said the UK and Canadian launches could be a way of placing pressure on the FDA by demonstrating that regulators in other countries found no fault with their product.

“Genetic testing is an important medical tool in certain situations, but for healthy people as a way to predict common complex diseases, it’s pretty useless,” she told BBC News.

“Most complex diseases and almost all the common ones – with some exceptions such as the BRCA 1 and 2 genes (implicated in breast cancer) – are multi-factorial with many genes and other biological, social and environmental causes.”

What happens to the data gathered by 23andMe also concerns some people. “It’s not entirely clear what their business plan is – whether they want to make money by selling kits to consumers, or whether they want to make most of their money by selling consumer data to other companies,” Prof Greely told BBC News.

But Ms Wojcicki believes the information provided to customers is empowering. “23andMe’s mission is to ensure that individuals can personally access, understand and benefit from the human genome,” she said.

Commenting on the announcement, Mark Thomas, professor of evolutionary genetics at University College London, said: “For better or worse, direct-to-the-consumer genetic testing companies are here to stay.

“One could argue the rights and wrongs of such companies existing, but I suspect that ship has sailed.”

Genetic testing of young bowel cancer patients could save lives

Autosomal dominant pedigree chart. In Autosoma...

Lynch Syndrome  (LS), formerly known as Hereditary non-polyposis colorectal cancer (HNPCC) is a familial cancer syndrome; affected individuals have disease-associated mutations in one of a number of key genes involved in normal DNA repair processes (most commonly the MLH1, MSH2, MSH6  and PMS2 genes). This results in a significantly increased risk of developing certain forms of cancer, notably colorectal (bowel) cancer but also endometrial and ovarian cancers and a number of others.

Teenager Stephen Sutton, who raised millions of pounds for cancer research, had a family history of the syndrome.  The test for this condition is used in some UK hospitals but has not been rolled out nationally. It is offered to all bowel cancer patients in Denmark, and to patients under the age of 70 in Norway and the Netherlands.

New research published as a formal Heath Technology Assessment has examined the efficacy and cost-effectiveness of alternative strategies to diagnose LS in patients with early-onset colorectal cancer – those younger than 50, 60 or 70 years of age.

Identifying LS has important health benefits for the patients – allowing appropriate close monitoring or preventative treatments for different forms of cancer as well as recurrences of colorectal cancer; for example, removal of the womb or ovaries in women. Moreover, cascade testing of close relatives can also identify family members at high risk of the same cancers who would benefit from risk reduction strategies.

The researchers compared the alternative approaches of microsatellite instability (MSI) testing or immunohistochemistry (IHC), including economic data. Analysis of the available evidence showed that testing for LS newly-diagnosed colorectal cancer patients aged under 70 years is indeed cost-effective. No specific method emerged as a clear ‘gold-standard’ for testing but the most cost-effective approach was found to be the use of MSI and BRAF mutation testing; cascade testing of at-risk family members was recommended for all strategies.

Efforts to review the alternative techniques and develop a consensus optimal strategy for national implementation have been in progress for many years.

The new HTA findings, combined with a new clinical classification scheme for genetic variants associated with LS released by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) earlier this year, should underpin policy changes that will increase the numbers of people identified with LS and prevent cancers.

Dr Ian Frayling of Cardiff University‘s Institute of Medical Genetics, one of the researchers, told the BBC: “Now the cost of genetic testing is coming down there is a good argument for younger bowel cancer patients to be screened. It will save lives and save money for the NHS”.

Looking further ahead, he and colleagues recommended new research into the cost-effectiveness of testing for LS in younger patients with newly diagnosed endometrial or ovarian cancer, and of the value of treatment with aspirin to reduce the risk of future cancers.

Deborah Alsina, chief executive of Bowel Cancer UK, said while bowel cancer is relatively rare in people under 50, 550 people in this age group lose their lives to the cancer each year.

“It’s critical that more lives are saved by ensuring people gain access to the screening surveillance they need, so that bowel cancer can be ruled out first, not last, in younger patients.”

23andme: Genetic Testing Saviour or Scam?

By Anthony Zurcher Editor, Echo Chambers

It seems like a life-changing innovation. Mail a swab with a bit of saliva off to a lab, and find out if you’re at risk for cancer, or Alzheimer’s, or some other genetically linked disease. What would you do with that information? Wouldn’t you want to know?

According to the Food and Drug Administration, however, it’s an idea that’s too good to be true.

The FDA came down hard on the company 23andme, which had offered just such a mail-order testing service. The company couldn’t ensure the reliability of its testing, the government contended. And without reliable test results, patients could seek unnecessary, possibly harmful treatments for non-existent conditions.

Two former Republican administration lawyers, David Rivkin and Andrew Grossman, don’t see it that way, however. For them, it’s about freedom of information: the government is trying to prevent patients from “knowing about their own health”.

Yes, they write in Tuesday’s USA Today, the field of genetic research is still developing, and the tests aren’t 100% reliable. “But that fact does not mean these services aren’t useful to consumers, particularly when combined with traditional diagnostics.”

“Rather than regulate by assuming that consumers are incapable of understanding their personal genetics,” they conclude, “the FDA should be thinking about the enormous opportunities to improve health offered by widespread, affordable genetic testing.”

“We need something like 23andme to help develop systems for letting people know how to deal with this genetic information, and for creating a world where people can actually start to deal with lots of health data”

Matthew Herper Forbes


MSNBC‘s Eric Rosenbaum agrees. “Look, health is no laughing matter, and the FDA is right to have concerns — especially given the predatory history of the medical and drug industry,” he writes. “Yet there’s a fine line between a regulator’s looking out for your best interest and one being a little overly paternalistic, or just behind the times.”

Forbes’ Matthew Herper would like to criticise the FDA’s decision, too, but he can’t. 23andme brought this on itself, he writes, by ignoring the government for six months.

“Either 23andme is deliberately trying to force a battle with the FDA, which I think would potentially win points for the movement the company represents but kill the company itself, or it is simply guilty of the single dumbest regulatory strategy I have seen in 13 years of covering the Food and Drug Administration,” he writes.

The government tried to work with the startup, he contends, but 23andMe made that impossible: “This is not the story of a big regulator choosing to squash a small company, but of a company that decided that it didn’t have to follow the rules.”

He concludes:

We need something like 23andme to help develop systems for letting people know how to deal with this genetic information, and for creating a world where people can actually start to deal with lots of health data. But outside of a crowd of libertarians and genoscenti, the company does not have the political support it needs for a fight against the FDA. And none of its high-minded ideals release it from the requirement the FDA wants to enforce: that a medical device has to work.

Mass-produced genetic testing is coming, and it’s going to get more reliable. If 23andme doesn’t deliver the breakthrough product, someone else will.

There are, however, two divergent views on what should happen next. Many medical professionals complain that the Internet has filled their examination rooms with self-diagnosing, second-guessing patients. If people can readily get their hands on details of their genetic makeup, that number could skyrocket.

Should the government have a firm hand in regulating the tests, possibly making them more expensive and less available? Or will people have cheap, easy, but largely unguided access to genetic data, and then have the freedom to act on that information as they so choose – even if their actions may not, in the end, be in their best interests?

What you don’t know won’t hurt you, as the saying goes. But what about what you do know?

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.

Variants of Uncertain Significance (VUS) and Lynch Syndrome (Patient Information Sheet)

This information sheet is available in pdf form by clicking this link Variants of Uncertain Significance

Lynch Syndrome is a genetic condition that carries a high risk of colorectal (bowel) cancer and other cancers. Individuals at risk for Lynch Syndrome can have genetic testing for it. The test may confirm a diagnosis and determine actions that can be taken. Results from genetic testing can also affect the perspectives of relatives who might also be affected.

What is a VUS? A variant of uncertain significance (VUS) is a genetic sequence change whose association with disease risk is currently unknown.

Most genetic test results are either ‘positive for a deleterious mutation,’ or ‘no mutation detected.’ However, as in many areas of medicine, results are occasionally inconclusive; consequently, medical management decisions are based on other contributing factors.

In the field of cancer genetics, clinicians and patients have encountered challenges related to the significance of unclassified genetic variants (UV) or variants of unknown significance (VUS). VUS are data that may not provide enough information to make decisions.  As the field of medical genetics moves toward whole genome sequencing (WGS), these challenges will inevitably become more frequent. VUS represent ambiguous and uncertain data, for which pathogenicity has not been demonstrated or excluded in published literature, mutation databases or on the basis of other clinical findings. Such variants present a clinical interpretation challenge and also evoke new counseling dilemmas for the understanding and psychosocial impact of uncertain genetic test results.

How do I manage a patient with a VUS? Since it is not possible to classify the genetic change as deleterious or benign, the patient should be managed based on personal and family history.

Individualized management may include increased surveillance and possibly other interventions, such as surgery or chemoprevention. Consider reviewing the case with your specialist to discuss appropriate management in the context of the specific patient and family history, and to explore whether additional work-up is indicated for the patient or family.

In  practice, patients may be screened as usual for Lynch Syndrome if the clinical history was suggestive of this, but we would currently be unable to offer presymptomatic genetics testing to unaffected relatives, unless the variant  was reclassified as a probable pathogenic mutation.

Result  No mutation detected (about 90% of results)  Variant, favor polymorphism (rare)  Genetic Variant of Uncertain Significance (rare)  Variant, suspected deleterious (rare)
 Negative  Almost certainly negative  Inconclusive  Almost certainly positive  Positive
 Cause of cancer in family has not been determined; patient may have increased cancer risk, but hereditary cancer less likely  Cause of cancer in family not likely due to this variant; patient may have increased cancer risk, but hereditary cancer less likely  May turn out to be positive or negative; physician will be notified once reclassified  Patient likely has the syndrome with cancer risks defined by the syndrome  Patient is confirmed to have the syndrome; cancer risks defined by the syndrome
 Manage based on personal and family history  Manage based on personal and family history  Manage based on personal and family history; provider should receive invitation for patient to participate in Variant Classification Program  Manage according to guidelines for syndrome; suggest single site testing for family members  Manage according to guidelines for syndrome; suggest single site testing for family members
What happens once a variant is reclassified?

Over time, a variant will often get reclassified as either a benign polymorphism or a deleterious mutation. When this occurs, an amended report is sent to the original ordering provider. While most clinical genetics centres proactively reclassify variants and communicates new findings to the original ordering providers, it is important to urge your patients with VUSs to keep in contact with your office or to notify the laboratory of an alternative provider if they move, so that they and their family can benefit from new information as it becomes available. 

Genetic testing: NHS ‘must back revolution’

BBCGenetic testing: NHS ‘must back revolution’

By James Gallagher, Health and science reporter, BBC News Jan 2012

Genetic code The cost of working out a patient’s genetic code is falling

Related Stories

Putting genetic testing at the heart of the NHS could herald a “revolution” in diagnosing, treating and preventing disease, according to the government’s genetics adviser.

Prof Sir John Bell has been presenting a report on how the NHS should prepare for advances in the field.

He said missing out would come at a high cost to patients.

Health Secretary Andrew Lansley has announced plans to speed up the introduction of genetic cancer tests.

One of the problems with modern medicine is that some of the definitions of disease are too broad.

Prof Bell told the BBC: “Breast cancer has always been defined because it is a tumour in the breast.

“But if you look at the molecular detail of those cancers, some are much more similar to ovarian cancers than they are to other breast cancers, in molecular terms and in terms of their response to therapy.”

Target treatment

Cancer drugs are generally effective in fewer than one in three patients who take them, the report says.

“Innovation in any setting has to deliver a much better product or lower cost, or both, and I think genetics may be one of the things that does both”

Prof Sir John Bell Chair of Human Genomics Strategy Group

The theory is that by looking at which genes are active inside a tumour, it will be possible to pick the correct treatment.

This is already happening in some cases. Bowel cancer patients with the defective gene K-RAS do not respond to some drugs, while the breast cancer drug herceptin works only if patients have a specific mutation, HER2.

One of the driving forces behind genetics in medicine is the plummeting cost of working out a patient’s genetic code. To sequence one patient’s genome once cost millions of pounds but it now costs thousands, and Prof Bell argues that in the future, the “cost could be essentially nothing”.

Prof Bell has previously accused the NHS of being “completely unprepared” for advances in the field of genetics. He has called for ministers to develop a strategy which would see the NHS adopting genetic tools, and training current and new staff in genetics.

He also wants a national centre which could store genetic information about patients who were sequenced. It would allow doctors to compare mutations in the genetic code with other patients who had the same mutation, to help plan treatment.

“We want to make sure that all patients can benefit from these tests”

Andrew Lansley Health Secretary

Prof Bell acknowledged that reforming the healthcare system to take greater account of genetics would require investment, but he added: “Innovation in any setting has to deliver a much better product or lower cost, or both, and I think genetics may be one of the things that does both.”

More testing

The government has yet to formally respond to the recommendations. However, Mr Lansley has announced plans to develop a new way of introducing and funding genetic tests for cancer.

“We want to make sure that all patients can benefit from these tests – as soon as the tests are recommended by NICE (the National Institute for Health and Clinical Excellence),” he said.

He compared the genetic code to a treasure map, saying the Xs were starting to appear, and that the promise of the field was “immense”.

The chief medical officer for England, Prof Dame Sally Davies, said genetics was “terrifically exciting” and would have an “increasingly important role” in areas such as cancer screening.

However, she said she was “quite worried” about some of the consequences, such the possibility that telling patients they had a low risk of developing lung cancer would give them a licence to smoke.


Family Health History | Genetic Alliance

Family Health History

A peek into the past can reveal a lot about your future.

Family health history is the story of diseases that run in your family. It is one part of the entire history of your family. Along with culture, values, environment, and behaviors, family health history influences the way you live your life. Learning about your family health history can help you make healthy choices: it is a cheap, easy way to improve your own health and the health of your family. Share the information you gather with your healthcare provider to further reduce your risk of disease and create a partnership around your health.

Check out the Does It Run In the Family? toolkit in English and Spanish! “A Guide to Family Health History” explains the importance of family health history, how to collect it, and how to organize it. “A Guide to Genetics and Health” explains genetics 101 and gives information on conditions that can run in the family, such as heart disease, diabetes, and cancer.

Customize these booklets for your family, organization, or community.

A Guide to Family Health History, English version, cover A Guide to Family Health History English

A Guide for Understanding Genetics and Health, English version, cover A Guide for Understanding Genetics and Health English

A Guide to Family Health History, Spanish version, cover A Guide to Family Health History Spanish

A Guide for Understanding Genetics and Health, Spanish version, cover A Guide for Understanding Genetics and Health Spanish

“A Guide to Family Health History” is also available in Chinese.

View several different versions on the Genetic Alliance YouTube Channel.

Tips For Collecting Your Family Health History

Learn all you can about your family’s health!

How do I collect family health history?

Talk to your family!

Holidays and other family events (birthdays, weddings, religious gatherings) provide a great opportunity to ask family members about their lives.

Plan individual conversations to get more information.

Use what you have—existing charts or trees, photo albums, baby books, birthday date books, etc.

Send a survey. This can be part of a holiday newsletter or school project.

What information should I collect?

Collect this information for you, your parents, siblings, and children, and then move on to the extended family:

  • name and relationship to you (myself, parent, child, etc.)
  • ethnicity, race, and/or origins of family
  • place and date of birth (or your best guess—for example, “1940s”)
  • if deceased, age and cause of death
  • health history—include conditions such as heart disease, diabetes, and cancer—and when the disease started
  • lifestyle (occupation, exercise, diet, habits such as smoking and regular doctor check-ups)

Collect stories about your heritage and culture. This is an excellent opportunity to preserve your family’s memories.

“Conversations about family health history should be ongoing, not a one-time topic to be discussed and forgotten. What you learn can shape your future and even save your life.”

Sharon Terry, President & CEO, Genetic Alliance

What should I do with the information I collect?

Bring it to your healthcare provider. S/he might refer you to a genetics specialist or recommend early screening.

Use it to make healthy lifestyle choices. You can change your diet and exercise habits to reduce your risk for many conditions.

Share it with your family. Shared knowledge can lead to support.

Keep adding to your family health history. It is a lifelong process!

For more family health history resources, click here.

via Family Health History | Genetic Alliance.


EGAPP™ Recommendation Statement: Genetic testing for Lynch Syndrome

EGAPP™ Recommendation Statement

EGAPP™ Recommendation Statement Adobe PDF file [PDF 219 KB]External Web Site Icon

“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

Summary of Findings on Genetic Testing for Lynch Syndrome for the General Public

General Public:
Genetic Testing for Lynch Syndrome

In 2009, the independent, non-federal Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working GroupExternal Web Site Icon reviewed the scientific evidence for genetic testing for Lynch syndrome (hereditary colorectal cancer) and developed a recommendation statement about the appropriate use of this testing. This brief summary of the EGAPP™ recommendation statement can help the general public understand what is intended by the EGAPP™ recommendation and where to find more information.

This information may be helpful for people with a recent diagnosis of colorectal cancer (cancer of the colon or rectum) and their close family members.

  • What is the purpose of genetic testing for Lynch syndrome for people newly diagnosed with colorectal cancer?

    Genetic testing is used to find out if a person’s colorectal cancer is hereditary (caused by an inherited gene change), so that family members can learn if they are also at increased risk.  This could help to protect them from getting this disease.

  • What is Lynch syndrome?

    About 3% of colorectal cancer cases are due to an inherited condition known as Lynch syndrome (sometimes referred to as hereditary nonpolyposis colorectal cancer or HNPCC).  People with this condition have a greatly increased chance to develop colorectal cancer, especially at a young age (younger than 50 years).  Children, sisters, and brothers of people with Lynch syndrome have a 50% chance to inherit the condition. Parents and other blood relatives such as grandparents, aunts, uncles, nieces and nephews are also at increased risk to have Lynch syndrome.

  • Who developed this recommendation?

    The EGAPP™ Working Group is a group of scientists and health care experts who review available research and evidence to make recommendations about the use of genetic tests.  This independent, non-government body includes representatives from universities, industry, clinical practice, insurance companies, and public health.

  • Did EGAPP™ recommend the use of genetic testing for newly diagnosed colorectal cancer patients?
    • YES:  The EGAPP™ Working GroupExternal Web Site Iconfound good scientific evidence to show that if individuals with colorectal cancer are found to have Lynch syndrome by genetic testing, their family members can benefit by:
      • undergoing genetic testing to learn if they are also at increased genetic risk.
      • if positive for the gene change, having earlier and more frequent screening which can prevent colorectal cancer.
    • They concluded that all people with a new diagnosis of colorectal cancer should be offered counseling and educational materials about genetic testing for Lynch syndrome.


Other Information

  • Are there other people the test might help?
    Although the EGAPP recommendation did not address use of testing in other situations, people with colorectal cancer diagnosed in the past (especially under age 50), and/or people with several family members with colorectal and/or uterine cancer may also benefit from genetic evaluation for Lynch syndrome.
  • How do I find out more about the condition/test?
    In addition to talking with your health care provider, the Web sites below provide additional information on colorectal cancer, Lynch syndrome, cancer genetic testing, and access to genetic counseling services.

    Health Professionals:
    More About the EGAPP™ Lynch Syndrome Recommendation

    This page contains more information about the EGAPP Lynch syndrome recommendation for health professionals.

    For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.

    EGAPP™ Evidence Review at a Glance

    Testing Approach Application Quality of Evidence
    Adequacy of information to address:
    Overall Recommendation*
    Analytic Validity Clinical Validity Clinical Utility
    DNA analysis of mismatch repair (MMR) genes: (MLH1, MSH2, MSH6, PMS2) Diagnostic Testing Adequate Convincing Adequate Sufficient evidence to recommend use for the benefit of relatives
    Microsatellite Instability (MSI) Preliminary (Screening) Test Convincing / Adequate
    Immunohisto-chemistry (IHC) Preliminary (Screening) Test Convincing / Adequate
    Methylation Status (BRAF V600E mutation) Preliminary (Screening) Test (Supplemental to IHC) Adequate

    *Overall recommendation was decided on the basis of a) evidence indicating moderate level of net health benefits to relatives, and b) contextual factors.

    EGAPP™ Recommendation Statement Adobe PDF file [PDF 219 KB]External Web Site Icon

    “The Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

    Considerations for Practice

    Note: See Contextual Factors Identified by EGAPP™ for more information.

    • All patients with a new diagnosis of colorectal cancer (regardless of age or family history) should be offered counseling and educational materials regarding genetic testing for Lynch syndrome.
      • The primary benefit will be the identification of relatives who also carry a gene mutation for Lynch syndrome. Affected relatives can be offered appropriate screening beginning at age 20-25.
    • Colonoscopy every one to two years is recommended for these patients and their relatives who test positive for Lynch syndrome beginning at age 20-25 years. Although there is not enough research to indicate that colorectal cancer due to Lynch syndrome should be treated differently than non-Lynch related colorectal cancer, individuals with Lynch syndrome are at increased risk for additional cancers and second primary colon tumors.
    • Individuals with colorectal cancer should be offered genetic testing even if there are no other family members with Lynch syndrome cancers. This is because family history was found to be less useful as a first step than strategies involving tumor testing in identifying Lynch syndrome in individuals with colorectal cancer. However, family history may still be an important decision tool for identifying individuals in the general population for referral to genetic counseling services to evaluate risk for hereditary colorectal cancer.

    See More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation.

    Testing Approaches

    Several testing approaches are potentially effective for identifying Lynch syndrome. DNA analysis has the highest sensitivity and specificity, but is also the most expensive. Most protocols directed at screening unselected colon cancers begin with preliminary testing of tumor tissue by MSI and/or IHC (with or without BRAF mutation).

    • Diagnostic testing: Typically performed on blood; identifies an inherited mutation in one of the Lynch syndrome genes.
      • DNA analysis (gene sequencing, deletion/duplication testing) for the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2.
    • Preliminary (Screening) Tests: Performed on tumor tissue; does not identify Lynch (MMR) gene mutations, but is used to guide subsequent diagnostic testing via DNA analysis.
      • MSI testing of tumor tissue: those with high instability either proceed to DNA analysis for MLH1, MSH2, MSH6, and PMS2 or to IHC testing.
      • IHC testing of tumor tissue: those with negative staining would proceed to DNA analysis of the gene/genes indicated.
      • Modification of Strategy 3, such that tumor tissue of patients with negative staining for MLH1 on IHC is tested for the BRAF V600E mutation to determine methylation status.  If the BRAF mutation is not found, the individual continues on for MLH1 DNA analysis.

    For more information about genetic testing approaches for Lynch syndrome, please see the National Library of Medicine, GeneReviews Web siteExternal Web Site Icon. (Note: This Web site does not necessarily reflect the opinions or recommendations of the Centers for Disease Control and Prevention or the EGAPP Working Group.)

    Contextual Factors Identified by EGAPP

    • Due to limited benefit to the colorectal cancer (CRC) patient, informed consent before microsatellite instability (MSI) or immunohistochemistry (IHC) testing is recommended.
    • There is no substantial evidence to show that identifying Lynch syndrome through routine genetic testing would lead to adverse psychological outcomes.
    • Evidence shows that there are relatively high levels of counseling and testing uptake among relatives and adherence to screening if patient is mutation positive.Top of Page

    Research Gaps Identified by EGAPP

    The EGAPP™ working group identified the need for research to address the following:

    • Better quality research regarding analytical validity of testing and laboratory proficiency testing;
    • Better quality studies evaluating clinical validity of various testing strategies;
    • Higher quality studies assessing clinical outcomes/clinical utility, effectiveness of screening;
    • Cost-effectiveness analyses to address testing strategies and impact on relatives
      (see More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation);
    • Studies to assess whether the clinical care and screening of CRC patients with Lynch syndrome should be altered.

    For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.


Life-Saving DNA Test Overlooked in Rise of Colon Cancer: Bloomberg News

from Bloomberg Business Week, By Robert Langreth and John Lauerman on October 24, 2012

Genetic testing is becoming cheaper and more widespread, promising to usher in a revolution in cancer treatment. Yet, long-standing DNA tests are often overlooked for reasons including doctors’ ignorance and financial incentives discouraging companies from marketing them.

Fifty years ago, Henry T. Lynch, then a medical resident in Nebraska, started tracking families with a high incidence of colon cancer and other tumors. While some were skeptical when he suggested the risks were inherited, geneticists proved him right in the mid-1990s by finding the genes that caused the condition. Lynch syndrome Hampel Discusses Failure to Test for Cancer Genesmay account for about 3 percent of all colon cancer, or more than 4,000 cases a year in the U.S., said Heather Hampel, an Ohio State University genetic counselor.


Hampel Discusses Failure to Test for Cancer Genes

A test for Lynch syndrome costs as little as $300. Still, only about 50,000 people have been diagnosed with the disease of 800,000 afflicted with it, according to Linda Bruzzone, president and founder of Lynch Syndrome International, a patient advocacy group.

“There are people dying needlessly,” Lynch, now 84 and director of the Hereditary Cancer Center at the Creighton University School of Medicine in Omaha, Nebraska, said in a telephone interview. “That is the horror of it.”

As scientists predict DNA testing will transform medicine, doctors and hospitals are ignoring existing tests that could help prevent thousands of cancer deaths, not just of their own patients, but in generations to come.

Little Training

Busy primary-care doctors, who typically have little training in genetics, don’t see the warning signs in patient family histories and don’t refer those at risk to a genetics expert. Testing companies don’t advertise and market some DNA tests as much as they do more lucrative tests for breast cancer genes, Bruzzone said.

This failure to incorporate genetic knowledge into routine prevention and treatment of diseases like colorectal cancer — the second-most common cause of cancer death in the U.S. –shows how hard it is to bring the benefits of the genome to patients.

“Lynch syndrome has been around for so many years, and we’re still not prepared to tackle it,” Fay Kastrinos, director of the hereditary gastrointestinal cancer program at Columbia University Medical Center in New York, said in a telephone interview.

Painful Lesson

Colleen Carroll learned that painfully. In 2002, Carroll, a computer programmer from Plainville, Connecticut, was diagnosed at the age of 36 with ovarian cancer, the same disease that killed her sister six years before. Her grandfather and two of his siblings earlier died of colon cancer.

Both types of cancer, and several others, are linked to Lynch syndrome, which speeds up tumor growth. Nevertheless, Carroll’s doctors never ordered a genetic test for it.

If they had, Carroll’s cousin might have been helped. She could have then undergone screening to spot cancer early or had her ovaries and uterus removed to prevent tumors in those organs. Instead, Carroll’s cousin died in 2006 at age 47 from ovarian and endometrial cancer.

“My cousin’s life could have been saved had I had the appropriate test,” Carroll, wrote to her doctors at Saint Francis Hospital and Medical Center in Hartford, Connecticut. “It is a horrible feeling.”

No company has exclusive rights to Lynch syndrome gene testing, and several companies offer the tests, including Myriad Genetics Inc. (MYGN) and Ambry Genetics Corp.

Doctor Education

As is often the case with generic drugs, companies are reluctant to pay for large marketing campaigns because of concern their efforts might not boost use of their own proprietary tests, Bruzzone said in a telephone interview. Consequently, many doctors don’t know the dangers of Lynch syndrome, she said.

“No company has enough of the market share to make it worthwhile to invest in education of doctors and patients,” Bruzzone said. “Without a strong base, you can’t get anything done.”

Sales from Myriad’s tests for Lynch and other hereditary colon cancers represented 9 percent of the company’s revenue in the year ended in June, versus 82 percent from its patent- protected tests for the BRCA1 and BRCA2 breast cancer genes.

Myriad and Ambry officials deny they skimp on marketing their colon-cancer gene tests.

Myriad Tests

Myriad “has invested substantially” in marketing and education for its Lynch syndrome test, which it has sold since 2000, said Mark Capone, president of Salt Lake City-based Myriad’s genetic-testing unit. He blamed complicated medical guidelines for Lynch syndrome tests, often involving a two-step testing process, and low patient awareness of colon cancer for underuse of the test.

Ambry Genetics, based in Aliso Viejo, California, markets Lynch syndrome testing to doctors and counselors through trade shows, conferences and talks, said Kurtis Glade, marketing director. Awareness of many genetic tests is relatively low among physicians, he said.

“We’re working to close that gap as much as we can with education,” he said in a telephone interview.

Doctors typically learn about new tests through a combination of scientific studies showing tests save lives, recommendations from specialist groups, and marketing and education sponsored by testing companies.

Family Trees

Unaware of the Lynch test, many primary-care doctors fail to see the warning signs in patient family histories like Carroll’s and don’t refer those at risk to a genetics expert, said Lynch, who continues to promote awareness of the condition he identified five decades ago.

Tracking down related cancers through scattered family members, finding tissues samples and ordering the genetic test can be “a hell of a lot of work” for busy physicians, Lynch said. “It doesn’t pay sufficient funds to warrant the excess of time.”

Even when doctors suggest testing, patients may forgo it for fear of stigma, although a 2008 law forbids employers and health insurers from discriminating on the basis of their DNA.

“There is a lot of fear and anxiety and apprehension” among patients, Lynch said. In some families known to carry Lynch syndrome, some relatives still put off getting the test for a decade or more, he said.

Claiming almost 50,000 lives in 2011, colorectal cancer cases often have no symptoms at early stages. More than 90 percent occur in people older than 50, according to the American Cancer Society.

Genetic Flaws

Patients with Lynch syndrome have flaws in one of four major genes that are involved in repairing DNA. As a result, precancerous growths in the colon, called polyps, can quickly turn deadly. Cancers in the endometrium, small intestine, stomach and ovaries can also grow unchecked.

About half of people with Lynch syndrome develop colon cancer by age 70, and as many as one-quarter of women with the condition develop ovarian cancer by that age, according to a 2011 study in the Journal of the American Medical Association. Affected women often have their ovaries and uterus removed after having children to prevent endometrial or ovarian cancer, and patients are told to have annual colonoscopies, which can prevent many deaths, said Richard Boland, a gastroenterologist at Baylor University Medical Center in Dallas.

Cancer Screening

In 2009, a study group sponsored by the U.S. Centers for Disease Control and Prevention recommended that everyone diagnosed with colon cancer should be offered testing to detect Lynch syndrome. Any relatives of patients who are positive for the defective genes should also be tested to prevent further cases, the panel said.

Still, just 42 percent of hospitals with cancer programs routinely screen colon cancer patients for the condition, according to a survey published this year in the Journal of Clinical Oncology. A separate study of 1,220 colon cancer patients found that only 5 percent got genetic testing for Lynch syndrome.

Doctors refer twice as many patients for investigation of possible inherited breast cancer to Houston’s MD Anderson Cancer Center than for possible hereditary colon cancer, even though the two are equally as common, said Patrick Lynch, a gastroenterologist at the center and the son of Henry Lynch. Colon cancer lacks the awareness that big-name charities like the Susan G. Komen for the Cure can give, he said.

Doctor Ignorance

“I talk to a lot of doctors, and most of them do not know what it is,” Neil Perlman, an internist in the Chicago suburb of Lincolnshire, said about Lynch syndrome.

Perlman knew little about the condition until 2009, when he was diagnosed with Lynch-related colon cancer at 44. His younger sister died of colon cancer in 2008, and his older sister had been found to have early uterine cancer in 2005. Before that, his mother had developed colon cancer in her early 50s.

Perlman had to have most of his colon removed and six months of chemotherapy. His cancer might have been diagnosed earlier, avoiding some of the heavy-duty treatment, had he or his sisters’ doctors understood the signs of Lynch syndrome in the family, he said. And his younger sister’s cancer might have been detected when it was more treatable, Perlman said.

It was frustrating that he and his sister went to good doctors and didn’t learn about the possibility of Lynch syndrome, Perlman said.

Culprit Emerges

When Traci Leopold started feeling a dull pain in her belly in 2002, she suspected it might be something serious. Her father and grandmother had died of colon cancer, and her uncle had suffered from it.

After a visit to her primary-care doctor, she was prescribed an anti-reflux medication for a hernia, she said. Months later, as the pain got worse, Leopold insisted on getting referred for a colonoscopy that revealed a rapidly spreading tumor. Leopold won’t name her former primary-care doctor.

Even then, her treating doctors never tested her for Lynch syndrome. It wasn’t until 2005, more than two years after Leopold donated tissue for an Ohio State University genetic study, that the culprit emerged. The results showed Leopold had Lynch syndrome.

“If they weren’t doing this study, I still wouldn’t know about Lynch syndrome,” said Leopold, a 39-year-old mother of two boys in Columbus, Ohio. “Genetics never came into my mind until they tested me.”

Richard Sheets, the gastroenterologist who performed Leopold’s colonoscopy, said he wasn’t aware of her family history when he first saw her. Once the tumor was found, the first focus was on treating it, not genetics, he said.

Little Awareness

While doctor knowledge of Lynch syndrome has improved since then, “there is no doubt that awareness is not where it needs to be yet,” he said.

Today, with her cancer in remission, Leopold receives annual colonoscopies, ultrasounds and other screening tests to spot new tumors before they spread. She also plans to make sure her sons get tested when they’re teenagers.

Since 2001, the average cost of deciphering a full human genome — the complete instructions for building the body — has dropped from $100 million to less than $10,000, according to the National Human Genome Research Institute. Testing for Lynch syndrome ranges from as little as $300, when the exact mutation that runs in the family is known, to as much as $4,000 when the mutation is unknown and multiple Lynch-causing genes need to be analyzed.

Lightning Strikes

When Colleen Carroll got ovarian cancer back in 2002, the only genes her doctors tested were BRCA1 and BRCA2, both widely known to be linked to breast and ovarian cancer. Those tests were negative. One doctor told Carroll, now 46, that her ovarian disease was a case of “lightning striking twice,” she recalled.

“I should have been referred to a genetic counselor,” Carroll said.

Carroll’s testing for these breast cancer mutations isn’t surprising, Bruzzone of Lynch Syndrome International said. Doctors and patients are well aware of the link between the BRCA genes and ovarian cancer because Myriad Genetics markets its patented test heavily, she said.

Hospital officials declined to comment directly on Carroll’s case. At the time she was treated, Saint Francis didn’t have cancer genetic counselors on staff, said Tina Varona, a spokeswoman. A program was established in 2010. The hospital’s protocols followed “the latest evidence-based procedures available at that time,” and some clinicians had supplementary genetics training starting in 2002, she said in an e-mail.

“In the early years of Lynch syndrome, everyone’s focus was much more on the colon cancer,” said Jonathan Sporn, chief of hematology/oncology at Saint Francis. “The potential role of non-colon cancer was not as emphasized as it is now.”

Not Lucky

Carroll survived because she had a less aggressive tumor that was caught and treated promptly.

Her cousin, Deborah Raboin, wasn’t as lucky.

In 2005, Raboin developed simultaneous ovarian and endometrial cancer. She was also treated at Saint Francis Hospital and was seen by at least one of the same doctors as Carroll. No one thought to test Raboin for Lynch syndrome, said her sister Karen Zeena.

It wasn’t until after Raboin died in 2006 and her father developed intestinal cancer that he was finally tested for Lynch syndrome by genetic counselor Ellen Matloff at Yale Cancer Center. The positive test led to screening of other family members, several of whom have been found to have Lynch syndrome genes. Carroll’s two nieces, the daughters of Carroll’s sister who died of ovarian cancer, have been screened and found to have Lynch syndrome genes.

“I feel like there were all these dots out there and nobody was connecting them,” Zeena said.

To contact the reporters on this story: John Lauerman in Boston at; Robert Langreth in New York at

To contact the editor responsible for this story: Jonathan Kaufman at

PLOS Genetics: Comparison of Family History and SNPs for Predicting Risk of Complex Disease

Authors: Chuong B. Do, David A. Hinds, Uta Francke, Nicholas Eriksson


The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)–based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%–30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history–based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalone disease prediction. On the other hand, we show that, unlike family history, SNP–based tests can reveal extreme likelihood ratios for a relatively large percentage of individuals, thus providing potentially valuable adjunctive evidence in a differential diagnosis.

Author Summary

In clinical practice, obtaining a detailed family history is often considered the standard-of-care for characterizing the inherited component of an individual’s disease risk. Recently, genetic risk assessments based on the cumulative effect of known single nucleotide polymorphism (SNP) disease associations have been proposed as another potentially useful source of information. To date, however, little is known regarding the predictive power of each approach. In this study, we develop models based on quantitative genetic theory to analyze and compare family history and SNP–based models. Our models explain the impact of disease frequency and heritability on performance for each method, and reveal a wide range of scenarios (16 out of the 23 diseases considered) where SNP associations may already be better predictors of risk than family history. Our results confirm the difficulty of obtaining accurate prediction when SNP or family history–based methods are used alone, and they show the benefits of combining information from the two approaches. They also suggest that, in some situations, SNP associations may be potentially useful as supporting evidence alongside other types of clinical information. To our knowledge, this study is the first broad comparison of family history– and SNP–based methods across a wide range of health conditions.

via PLOS Genetics: Comparison of Family History and SNPs for Predicting Risk of Complex Disease.

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