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American College of Medical Genetics and Genomics (ACMG) technical standards and guidelines for genetic testing for inherited colorectal cancer


Read the original article in Genetics in Medicine (2013) Hegde et al

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome—with extracolonic features—and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir–Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.

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A national survey of hereditary colorectal cancer services in the United Kingdom


Autosomal dominant pedigree chart. In Autosoma...

A new study has just been published in the journal Frontline Gastroenterology.  This shows a highly inconsistent approach to the management of patients at elevated risk of hereditary colorectal cancer (CRC) in the United Kingdom (UK). 

The British Society of Gastroenterology (BSG) Cancer Group designed a national survey to determine how we might understand and improve the service for these patients.

What is already known on this topic? Genetic factors contribute about 35% of all colorectal cancer (CRC) risk.  There is good evidence that the correct management of patients with an elevated hereditary risk is a highly effective method of preventing CRC.  This can be achieved by screening according to guidelines and the development of a high quality service with clear patient pathways.  However in some studies there is evidence of an inconsistent approach to the management of those patients, with low risk patients being screened too often, and high risk patients not frequently enough.  There is also a low referral rate to genetic services for high risk patients.

What this study adds? Responses to this national survey suggest a poor understanding of the current guidelines amongst clinicians and variable clinical pathways for patients.  There is also a perception that another unspecified clinician is undertaking this work.  This may explain the wide variation in care and low adherence to guidelines in the United Kingdom (UK).

How might it impact on clinical practice in the foreseeable future? We recommend the development of clear structures and the provision of a high quality service to these patients through national audit, development of quality standards and education of physicians and surgeons in the UK.  Each hospital should develop a lead clinician for the delivery of these services.  Only in this way will this ad hoc approach to the management of hereditary CRC be improved.

Study Reference: Kevin Monahan & Susan Clark.  Frontline Gastroenterology. 2013 Online First

Abstract 

Objectives: The British Society of Gastroenterology (BSG) Cancer Group designed a survey to determine how we might understand and improve the service for patients at elevated risk of hereditary colorectal cancer (CRC).

Design and Setting: United Kingdom (UK) gastroenterologists, colorectal surgeons, and oncologists were invited by email to complete a 10 point questionnaire. This was cascaded to 1,793 members of the Royal College of Radiologists (RCR), Association of Cancer Physicians (ACP), the Association of Coloproctology of Great Britain and Ireland (ACPGBI), as well as BSG members.
Results:  Three hundred and eighty-two members responded to the survey, an overall response rate of 21.3%. Although 69% of respondents felt there was an adequate service for these higher risk patients, 64% believed that another clinician was undertaking this work. There was no apparent formal patient pathway in 52% of centres, and only 33% of centres maintain a registry of these patients. Tumour block testing for Lynch Syndrome is not usual practice. Many appeared to be unaware of the BSG/ACPGBI UK guidelines for the management of these patients.
Conclusions: There is wide variability in local management and in subsequent clinical pathways for hereditary CRC patients. There is a perception that they are being managed by ‘another’, unspecified clinician. National guidelines are not adhered to. We therefore recommend improved education, well defined pathways and cyclical audit in order to improve care of patients with hereditary CRC risk.

My Semicolon Life: It’s not just your cancer by Brian Mansfield


My Semicolon Life: It’s not just your cancer

When USA TODAY’s Nashville music critic Brian Mansfield was diagnosed with colon cancer at age 48, he figured that a lifetime of Southern-fried foods, extra-large sodas and stress eating on deadline had brought it on. Turned out he had a genetic syndrome that gave him an 80% chance of developing colon cancer. He’ll chronicle his life with the disease — and with only a small part of his colon — in a series of weekly installments.

  • USA TODAY reporter Brian Mansfield and his family. Clockwise, from top: Brian Mansfield, Nick Mansfield, Annalise Mansfield, Gracelyn Mansfield, Zac Mansfield. Nancy Mansfield is in the center.USA TODAY reporter Brian Mansfield and his family. Clockwise, from top: Brian Mansfield, Nick Mansfield, Annalise Mansfield, Gracelyn Mansfield, Zac Mansfield. Nancy Mansfield is in the center.

When I received my colon-cancer diagnosis in June, my surgeon wanted to test me for Lynch syndrome. A genetic disorder that’s the most common cause of inherited colorectal cancer, Lynch syndrome accounts for about 4,200 new cases of colorectal cancer each year, or between 2% and 5% of all cases. The patients who carry it, however, often look an awful lot like me, people in their mid- to late 40s.

Determining whether or not I had Lynch would affect the course of my treatment. If I didn’t have it, my surgeon would remove the tumor and several inches of colon to either side. If I tested positive, on the other hand, the likelihood of new tumors was so high that he would want to take out more. On the theory that the less colon I had, the less place there’d be for a tumor to recur, he would remove all but the last couple feet of my colon and rectum, just enough to keep me from needing a colostomy bag. Because of Lynch’s hereditary nature, a positive result also would have a big impact on my family.

It wasn’t a cheap test, my doctor said, about $4,000, and my insurance might or might not cover the cost (it did). Since nobody in my immediate family had ever had colon cancer, I figured the test would come back negative. Still, better to err on the side of caution now than have to undergo a second surgery because I wanted to do some cost-cutting.

Three months ago, I’d never heard of Lynch syndrome. But that didn’t stop me from having it.

Now I know more about it than I wish I did. The syndrome — named after Henry Lynch, a geneticist who has done groundbreaking research on hereditary cancer at Nebraska’s Creighton University — put me at an elevated risk for developing colon cancer. It’s also called HNPCC, or hereditary nonpolyposis colorectal cancer, but, to quote Leslie Nielsen in Airplane!, “that’s not important right now.”

What is important is that as many as 800,000 people in the USA may have this disorder. According to the national Centers for Disease Control and Prevention, as many as 98% of them may be undiagnosed, as unaware of their condition as I was.

Lynch syndrome is a defect in one of the mismatch repair genes, which correct errors during DNA replication. It’s like using a broken photocopier with no quality control, endlessly churning out flawed copies. Stack those flawed copies high enough, and they turn into a tumor like the one removed from my abdomen last month.

That tumor’s gone, but my copier’s still broken. There’s a 50/50 chance a new tumor will crop up some time in the next 15 years, if not in my colon, then maybe in my stomach. Or my small intestine, my urinary tract, or even my brain.

In general, Lynch syndrome carriers have an 80% chance of getting colorectal cancer during their lifetime. For women, that percentage is slightly lower, but their chances of getting endometrial cancer run as high as 60%. My particular variety of Lynch (there are several) comes with a slightly lower risk of colorectal cancers (fat lot of good it did me) but a much higher risk of gynecological cancers for women.

Though Lynch plays a part in only a small percentage of colon cancers, it’s more likely in cases where the patient is under 50. When there’s no immediate family history — as was the case with me — the likelihood of Lynch rises to 7%, according to my surgeon. Factor in a family member with colon cancer, and the chance that Lynch is involved goes up to about 30%.

Linda Bruzzone, founder of Lynch Syndrome International, was diagnosed with Stage 3 colon cancer in 2007 at age 55. Her brother, sister, father and an aunt all had Lynch-related cancers. She founded LSI in 2009 when “we couldn’t find anybody alive with the Lynch syndrome gene,” she says.

That all changed when the organization went online. “Things went absolutely berserk,” Bruzzone says. Now, in addition to the website, LSI maintains a Facebook page, and Bruzzone describes the culture of Lynch-cancer survivors and previvors that gathers there as a hopeful one.

My family already has benefited from our new knowledge. My father, who almost certainly passed this trait to me, had never had a colonoscopy, even though he’s 74. Since my diagnosis, he and my younger sister have both had their first colonscopies, and both had polyps removed. Left alone, those polyps could have turned cancerous within a couple years. (Polyps in people with Lynch tend to turn into cancer on a faster basis, my surgeon says.)

What signs might indicate Lynch syndrome in your family? Check your family medical history for three relatives with colorectal or gynecological cancers, especially if any of them were younger than 50 when they were diagnosed. The cases should span successive generations and also include at least one first-generation relative (a parent, sibling or child).

That last detail was the one that tripped me up. My paternal grandmother’s extended family had cancer all through it, but she’d had a hysterectomy in her 50s, thereby removing her most at-risk organs. My father was an only child. Since he and my sister had never had colonscopies, even if they had had cancer, none of us would have known.

At some point, my wife and I will get tests on our four kids, the oldest of whom turns 21 next month. Each has a 50/50 chance of carrying the gene. The ones that do probably will have colonoscopies every couple of years starting in their early 20s. Endoscopies, to check for cancer in the upper gastrointestinal tract, will start around 30. The girls also will be screened regularly for gynecological cancers, most likely using a combination of ultrasounds and biopsies. Barring a major medical advance, their doctors may recommend preemptive hysterectomies when they reach their 30s.

There’s a pretty good chance I’ll be around to watch them go through all that, and listen as they blame me for it. My heart will ache for them every time, but I’ll happily take the grousing about colonoscopy prep, or even a life-altering surgery, to keep them from having to hear the words “We found cancer.” I may have bought my father a few extra years; maybe my situation can buy my kids a whole lot more.

It’s like Bruzzone told me: “The difference in our generation and the previous one is that we’re surviving.”

Music that makes me want to live

Cancer has changed the way I hear music, more than any other life event except my marriage. Songs I once appreciated only on a surface level now strike deep at the core of my soul. Some inspire me; some terrify me. Others that I might have liked before, I’ve got no use for now. I’ve also got more time to listen, whether it’s during my morning exercise time or while lying in a hospital bed. These songs form part of the soundtrack to my cancer story.

1. Stories to Tell, Dave Barnes

2. Lifetime, Emeli Sandé

3. Don’t Let Me Fall, The Bluefields

4. If You Ever Get Lonely, Love and Theft

5. From There to Back Again/Pacific Coast Highway/Summer’s Gone, The Beach Boys

Lifestyle and Reducing Your Risk of Bowel Cancer (Video)


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