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My Semicolon Life: Crossing the finish line with cancer by Brian Mansfield

My Semicolon Life: Crossing the finish line with cancer

USA TODAY‘s Nashville music critic finishes a chapter of his cancer story with a successful 5K run.

6:29AM EDT October 27. 2012 – 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.

The chili-pepper boxers hadn’t come out in ages.

I bought them in Austin a good 20 years and about that many pounds ago. They never were practical for everyday use because, well, they don’t open in the front. I think I keep them only because they remind me of a dear friend who died too young.

Maybe that, and the fact that they don’t open in front, is why they seemed the perfect choice to wear at last weekend’s Undy 500 in Nashville. The run, which raises funds for the Colon Cancer Alliance, encourages participants to run in boxer shorts.

I look ridiculous in them, of course. Not even my black Johnny Cash T-shirt — another article of clothing I couldn’t fit into four months ago — made me look less silly, especially once I added the black knee-high compression socks I bought to help keep me from tearing any more calf muscles. But after posting detailed accounts of my bodily functions here and on Facebook for the past four months, I don’t embarrass easily.

Fortunately, friends from nearly every part of my life — from high school, from work, from my neighborhood — were willing to not only be seen with me, but to wear their own boxers and run.

One in particular, my pal Cindy, has never been more than a phone call away since the very start. If I remember correctly, I had to cancel lunch with her the day I got my diagnosis. We were part of a weekly lunch group, but I had no idea then that she’d be one of the first people to visit me in the hospital and to bring food to my family when I got home. As a runner who’d recently completed a half-marathon, she even agreed to pace me on the 5K.

Having not had a good run in three weeks because I kept getting hurt, the run concerned me, especially when I realized the course’s first mile went uphill. We started in front of the Country Music Hall of Fame and went straight up Demonbreun Street to Musica, a giant statue of dancing naked people you may have noticed recently on ABC’s Nashville during a video shoot for Hayden Panettiere’s character. The next mile cut through the Music Row area, going down 17th Avenue South to Edgehill Avenue — which, I didn’t realize until I had to run it, is so named because it’s on the edge of a hill — up to 16th Avenue South, then to Musica again. From there, it was all downhill, which was good, because by the time I got back to Musica, I felt like I was ready to throw up.

Cindy might have let me throw up, but she wasn’t about to let me stop. We started too fast because we didn’t want to run in a crowd. When she realized we were on track to make my dream pace — a goal I’d all but given up when injuries prevented me from training — she kept encouraging me, giving me our times at each mile marker, moving in front of me on the inclines so I could watch her feet instead of staring at the top of the hill, reminding me in the last stretch that “You can do anything for four minutes.”

Friends like Cindy have helped me all through my journey with cancer. From simple, reassuring Facebook posts to offers of substantial amounts of money, support has come from all over — from people I loved, from people I admired, from people I hardly knew. Most often, it came from places I wouldn’t have expected. I used to think I had a hard time making friends; now I realize I just had a hard time recognizing them.

According to Cindy’s running app, we crossed the finish line nine seconds under my dream goal: 29 minutes, 51 seconds. The official time had me just over, 30:20 — a reminder to never, ever slow down when the finish line’s in sight, no matter how well you think you’re doing. Either way, I couldn’t possibly have done that before my diagnosis. I guess that means I’m healthier now than I was before I had cancer.

My cancer story’s not over, though. I’ve only finished this chapter. Because of my genetic disorder, a new cancer is always a possibility; the scar across my bellybutton and the changes to my digestive process are daily reminders that my life will never be the same as before this summer and could suddenly change again. I can do things to minimize the likelihood that new tumors will grow. With my doctors, I can keep a vigilant watch to catch future problems early. But even if I never receive a troubling test result, in my mind cancer will never be farther away than just around the corner. There’s always a better-than-average chance that it’ll be what eventually takes me out.

I don’t think about beating cancer, though. We’re not in a competition. I absolutely understand why some people approach treating cancer like waging war, but, to me, it’s not a battle; it’s more of a workaround situation. Besides, right now, I don’t have cancer. I have Lynch syndrome.

Cancer is just a complication.

Music that makes me want to live

Cancer has changed the way I hear music, more than any other life event except 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. This week’s soundtrack to my cancer story comes from some of the musicians the world has lost to cancer. I admired all of them, and I knew far too many of them.

  1. Drift Away, Dobie Gray
  2. All Things Must Pass, George Harrison
  3. And When I Die, Laura Nyro
  4. Redemption Song, Bob Marley and The Wailers
  5. Last Dance, Donna Summer
  6. Turn Off the Lights, Teddy Pendergrass
  7. Inside My Love, Minnie Riperton
  8. Son of a Preacher Man, Dusty Springfield
  9. I Just Want to Love You, Eddie Rabbitt
  10. The End of the World, Skeeter Davis
  11. Green, Green Grass of Home, Porter Wagoner
  12. Blue Suede Shoes, Carl Perkins
  13. And I Love Her, Chet Atkins
  14. Wysteria, Dan Fogelberg
  15. When I Go Away, Levon Helm
  16. There Is a Light, Duane Jarvis
  17. Walk By Faith, Stephen Bruton
  18. Keep Me in Your Heart, Warren Zevon
  19. One Dyin’ and a Buryin’, Roger Miller
  20. What a Wonderful World, Joey Ramone

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

My Semicolon Life: Welcome to the cancer club by Brian Mansfield

My Semicolon Life: Welcome to the cancer club

By Brian Mansfield, Special for USA TODAY

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.

  • Melissa Mitchell, left, and USA TODAY Nashville correspondent Brian Mansfield have Lynch syndrome, which increases the risk of colon and other cancers.Melissa Mitchell, left, and USA TODAY Nashville correspondent Brian Mansfield have Lynch syndrome, which increases the risk of colon and other cancers.

Jill Chang remembers the poster about Lynch syndrome that hung in her physician’s office. “Does cancer run in your family?” it asked in bold letters of warning-sign red. Cancer did run in Chang’s family, and as she read about the types — colon, uterine, stomach, ovarian —most often associated with the hereditary genetic mutation, the 40-year-old mother of two thought, “Oh, my gosh, this looks like my family.”

If Chang, now 41, had known sooner that she carried Lynch syndrome, she would have done things differently. When she underwent her colon cancer surgery at age 30, she would have opted for a pre-emptive hysterectomy at the same time. Then she wouldn’t have had endometrial cancer last year. She wouldn’t have had to undergo that round of chemotherapy. Her curly blond hair would never have fallen out.

I met Jill and others with Lynch syndrome this past week at a seminar to train us to speak on behalf of people with this genetic disorder that affects as many as 800,000 people in the USA, more than 90% of whom don’t even know they carry it. I previously had exchanged Facebook messages with a few people who carry the mutation, but I hadn’t encountered them in person. Now I know their faces, their families and their fears.

Diane Shak let a doctor’s horror stories about hysterectomies and double mastectomies scare her away from genetic screening nearly 20 years ago, after her brother’s colon cancer diagnosis. Only after an older sister’s diagnosis of both Lynch syndrome and colon cancer did Shak get her own test.

Melissa Mitchell’s family knew that cancers ran among them, they just didn’t know all the different types were related. Mitchell, who is working on a second bachelor’s degree in criminal justice, can trace her cancer history back to 1867, and many of her relatives died in their 20s and 30s. Eleven members of her family have been tested for Lynch syndrome. Seven tested positive; three have had cancer. Mitchell had colon surgery four days after her Lynch diagnosis in May 2011.

The broken genes of Lynch syndrome most often result in colon or, in women, uterine cancers, but it puts carriers like me at an elevated risk for a variety of cancers. It can manifest itself in many ways. Miriam Masia, for instance, a music therapist from Miami, got diagnosed after having seven aggressive skin cancers removed. Cindy Timms, a theater and debate teacher in Texas, had a long history of tumors and migraines before developing colon cancer.

Laura Simonetti has never had cancer, but her father did. After her father underwent his third major surgery for colon cancer, a nurse recommended genetic testing to Simonetti. Together with a genetic counselor, she mapped out her family cancer history, gathering stories of illnesses from aunts, uncles and cousins. One week after the birth of her daughter, Simonetti tested positive for Lynch in December 2007. Now in her mid-30s, she’s considered having a hysterectomy to prevent the occurrence of uterine or ovarian cancer (she’s decided to wait).

Those of us who came together journeyed from a dozen different states. At 48, I was right in the middle of the group, age-wise, but I was also the newbie, since I received my Lynch diagnosis just two months ago. Some of them have been living with their diagnosis for many years and through multiple treatments.

Whatever differences we may have — age, gender, ethnic background, number of primary tumors — one thing we all have in common is our concern for our families. Having a name and a reason for our predisposition to cancer allows us to do something about it, not only for ourselves but for those around us. It allays our fears with hope.

I like to think that I bought my father a few years when his first colonoscopy, at age 74, revealed two polyps, one of them very large. Gene von Mosch, a financial planner, is convinced that he saved the life of his 27-year-old daughter, who was diagnosed with colon cancer after a positive Lynch test.

Diane Hardesty runs a bookkeeping and tax practice and uses a spreadsheet to track her family’s cancer history. She knows of 13 family members who have had cancer, 10 of whom have died. Not one of those deaths occurred after her family learned about Lynch syndrome. Hardesty’s doctors have caught pre-cancerous areas of her body six times. Thanks to vigilant screening because of her Lynch diagnosis, none of them have ever turned into cancer. She now advocates tirelessly on behalf of Lynch screening.

Five generations of Chris Moyer’s family have had hereditary cancers, including a cousin who died of brain cancer at 19. Moyer had his first colonoscopy when he was 21. He’s now 32 and has had a total of three. After his mother’s diagnosis with Lynch, he expected to need colonoscopies every two to three years for the rest of his life. But he tested negative for Lynch. As a result, Moyer is done with colonoscopies for a while. He won’t have to get another until he’s 50. And neither will his two sons.

If your family history looks like any of ours, you know how relieved he is. And if your family history looks like ours and you haven’t been screened for hereditary cancers, you might consider talking to your physician about it.

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. Even If It Breaks Your Heart, Eli Young Band

2. Sweet Spot, Tift Merritt

3. Worry Walks Beside Me, Michael Kiwanuka

4. Safety Line, Sixpence None the Richer

5. When I Saw You Leaving (For Nisey), Alan Jackson

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

Lifestyle and Reducing Your Risk of Bowel Cancer (Video)

Aspirin for Hereditary Colorectal Cancer

The study shows that regularly taking the medicine cuts the risk of bowel cancer by more than 60% in those with a particular genetic predisposition to get the disease – as well as reducing the risk of other hereditary cancers.

Scientists who led the study said people with several family members with cancers other than breast, blood and prostate might be advised to start taking aspirin daily from the age of 45.

They said those without a family history of the disease might also consider doing so, but that they should make a personal assessment of the risks and benefits and get medical advice. Anyone thinking of taking the drug regularly should consult their doctor first.

Doctors already prescribe low, daily doses of aspirin to people at increased risk of heart attacks and strokes, and evidence has been growing of anti-cancer properties for 20 years. However, this is the first long-term, randomised controlled trial to show such an effect.

The trial involved people with Lynch syndrome, a genetic abnormality that predisposes carriers to develop bowel cancer and other solid organ cancers including endometrial, ovarian, stomach, kidney, oesophageal, brain and skin tumours.

The condition affects at least one in 1,000 people. Carriers are around 10 times as likely to develop cancer and often do so at a young age.

Professor John Burn of Newcastle University, who led the study, estimated that if all 30,000 or so people with Lynch syndrome in the UK were to start taking two aspirin tablets a day then some 10,000 cancers would be prevented over the next 30 years, saving about a thousand lives. The downside of the treatment is that around an extra thousand people would develop stomach ulcers as a side-effect.

“People with a genetic susceptibility are a model system,” said Burn, whose work is published online in the Lancet on Friday. “They are more sensitive to the environmental triggers to cancer.

“If we can do something to change cancer progression in people at high genetic risk, then that’s telling us what we might all benefit. But we are not making a recommendation for the general population. Everyone can take this evidence and make their own choice.

“In between you have the people who have a family history [of cancer]. Those individuals may well decide to put themselves on aspirin and that would be a reasonable conclusion from the data currently available.”

Between 1999 and 2005, about half of a group of 861 Lynch syndrome carriers were given two aspirins (600mg) a day, while the rest took placebos.

By 2010 those who had taken aspirin for at least two years were 63% less likely to have developed bowel cancer.

Looking at all forms of the disease, almost 30% of those in the placebo group developed a Lynch syndrome-related cancer, compared with 15% for those given aspirin.

The most common side effects associated with taking aspirin are gastrointestinal ulcers and stomach bleeding. There is also an very small increased risk of haemorrhagic stroke, in which a blood vessel in the brain bursts.

There was no difference in the proportions of the study groups suffering such side-effects.

Burn added that he takes low-dose aspirin tablets as a preventative measure. “That was a balanced judgment based on weighing risks and benefits. I know I might get an ulcer or a cerebral bleed but I’d rather not have a heart attack, stroke or cancer. That’s my choice.”

Aspirin is a synthetic version of the active component of willow bark, salicylic acid, which has been used as a medicine for its anti-inflammatory properties for hundreds of years. Salicylates also trigger programmed cell death to help diseased plants contain the spread of infection.

“It’s not a huge stretch to think that if salicylate induces programmed cell death in plants to kill infected cells, maybe it’s doing similar things in the animal kingdom to enhance the death of aberrant cells causing cancer,” said Prof Burn.

“This adds to the growing body of evidence showing the importance of aspirin, and aspirin-like drugs, in the fight against cancer and emphasises how critical it is to carry out long-term international research,” said Prof Chris Paraskeva, a bowel cancer expert at the University of Bristol.

The CAPP team have launched a website to recruit 3,000 people with Lynch syndrome worldwide to take part in a five-year trial to determine the best dose of aspirin to take.


My Semicolon Life: 5K prep tougher than cancer surgery, by Brian Mansfield

If I’ve learned one thing in recent weeks, it’s that I can put up with almost any kind of pain for an hour.

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.


How in the world am I having a harder time getting ready for a 5K than I did recovering from cancer surgery?

This weekend, I’m supposed to run in the Colon Cancer Alliance’s Undy 5000 Nashville run. Participants are encouraged to run in their boxer shorts. I’ve got a pair with chili peppers on them that I bought about 20 years ago. They’re still a little snug, but I think they’ll work.

I’ve been planning this since shortly after my diagnosis in June. At first, I expected to be in the middle of chemo treatments and have to walk it. When I found out that chemo wouldn’t be necessary, I started planning to run.

COLUMN: Last week’s installment

MORE: Follow Brian on Twitter

PLAYLIST: Music that makes me want to live

Initially, my training went well. Before I left the hospital, I was walking a mile a day, albeit in several short bursts. I kept walking when I got home; within a month, I could cover 5 miles in a wide loop around my neighborhood.

My first attempts at running hurt a little, jostling inner parts that hadn’t quite settled into their new positions. Eventually, though, I settled into a nice training regimen, alternating days of walking and days of running.

By mid-September, I had figured out a stride that felt natural. Apparently, my body operates at 150 beats per minutes. Maybe it has something to do with coming of age during the early ’80s: Several of the records that I remember causing the most visceral responses — R.E.M’s Radio Free Europe, Bruce Springsteen’s No Surrender, The Cure’s Just Like Heaven, not to mention Twister Sister’s We’re Not Gonna Take It and Quiet Riot’s Cum on Feel the Noize cover — all operate within a couple beats of 150 bpm. That tempo would put me on pace for a 30-minute 5K, which felt too good to be true of my first official run.

Just as I got to where I could run the right distance, run the right time, my body started falling apart.

My feet went first, developing tender spots just below the outer side of both ankles that made standing and walking difficult. I targeted a pair of overworn shoes as the culprits and threw them away, but the pain kept me off the street for a week.

Then, I tore a calf muscle during my first run back. Five houses from home, with my earbuds in, I heard the pop. The injury slowed me down enough that my wife and daughter could keep up with me when we went to New York a couple of weeks ago for a surgery-delayed vacation.

The morning we left New York, I cracked a tooth all the way down one root, biting into a slice of pizza. Before I could have an oral surgeon extract the tooth, I spent several days trying to maintain the fine line between passing out from pain and throwing up from pain meds. I got the balance wrong one day and had to cut short an interview, vomiting before I could return the phone to its cradle.

Wednesday night, I went for my first run in two weeks. From my first steps, I could tell my body wanted to run. My feet did exactly what they were supposed to, hitting right behind the ball, rolling forward and flipping back. I didn’t push myself at all, and my movement felt like an easy glide.

A few minutes in, though, and I started feeling every little twinge in my leg. Maybe a muscle was acting up, or maybe I was gun-shy, allowing my imagination to run away with me. Either way, I didn’t want to take any chances, so I eased up on my pace — running three minutes, walking three minutes.

Then, during the song that was playing when I tore that muscle two weeks ago — Joan Jett’s version of ZZ Top’s Tush — my left calf started seizing up again. Not enough to stop me, but enough to spook me. By the time I got home, my right leg had started pulling tight, too.

I went out again Thursday but took it real easy, going about 2 miles but running maybe a third of it. Right now, my calves are so tight that, if my muscles were guitar strings, I wouldn’t need a capo to raise the pitch. It’s not the kind of feeling I want to take into a 5K run.

But if I’ve learned one thing in recent weeks, it’s that I can put up with almost any kind of pain for an hour.

All I have to do is keep moving.

Music that makes me want to live

Cancer has changed the way I hear music, more than any other life event except 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. Meant to Live, Switchfoot

2. Get On Your Boots, U2

3. Run Run Run, The Explorers Club

4. Everybody Talks, Neon Trees

5. Cruise, Florida Georgia Line

6. Enola Gay, Orchestral Manoeuvres in the Dark

7. Constructive Summer, The Hold Steady

8. Believer, Goldfrapp

9. Something’s Got a Hold On Me, Etta James

10. Use Me, Bill Withers

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.

A trial of methotrexate for cancer that has spread in people with a faulty MSH2 gene (MESH)

A trial of methotrexate for cancer that has spread in people with a faulty MSH2 gene (MESH)

This trial is looking at the chemotherapy drug methotrexate for people with a MSH2 gene fault who have cancer that started in the bowel, stomach, womb (endometrium), bladder, or lining of the urinary system (urothelium) and has spread.

Every cell contains DNA. This is the genetic information which controls how cells behave. In cancer cells, the DNA is changed or damaged. Cancers can have different types of changes in the DNA. One of these is when a gene called MSH2 is not working properly.

Doctors often use chemotherapy to treat cancer. But sometimes the cancer comes back after treatment and spreads elsewhere in the body.

Methotrexate is a chemotherapy drug that is used to treat some types of cancer. We know from research that methotrexate kills cancer cells when the MSH2 gene is not working properly. Researchers want to find out if it will help people with a faulty MSH2 gene who have cancer that has spread.

The aims of this trial are to

  • See how much methotrexate helps people in this situation
  • Learn more about the side effects


Start 08/04/2009

End 08/04/2014


Phase 2

Who can enter

You can enter this trial if you

  • Have cancer that started in your bowel, stomach, womb, bladder or urothelium and has grown into surrounding tissue, or has spread elsewhere in the body
  • Have cancer that did not respond to, or has come back after, treatment with standard chemotherapy, or you cannot have standard treatment for some reason
  • Have a MSH2 gene fault (the doctors will do tests to confirm this)
  • Have satisfactory blood test results
  • Are well enough to take part in the trial (performance status 0, 1 or 2)
  • Are at least 18 years old
  • Are willing to use reliable contraception during the trial and for 6 months afterwards if there is any chance you or your partner could become pregnant

You cannot enter this trial if you

  • Have already had treatment with methotrexate unless it was for a non cancerous condition and you finished treatment at least 5 years before you were diagnosed with cancer
  • Have had any other cancer in the last 10 years apart from non melanoma skin cancer or carcinoma of the cervix and the trial doctor thinks this could affect you taking part in this trial (If you have Lynch syndrome, you may be able to take part if you have had other cancers – the doctors will advise you on this)
  • Have had radiotherapy to a single area of cancer (a lesion) that the researchers will be measuring in this trial, unless the lesion has got bigger since you had radiotherapy
  • Have another medical condition that cannot be controlled with medication
  • Are pregnant or breastfeeding

Trial design

This phase 2 trial will recruit 56 people. Everybody taking part will have methotrexate.

You have methotrexate as an injection into a vein. The treatment only takes a few minutes. You have another injection a week later and then 2 weeks without any treatment. Each 3 week period is called a cycle of treatment. You have up to 6 cycles of treatment. But if the treatment is helping you, your doctor may talk to you about having it for longer.

During the trial, the researchers will take samples of blood, urine and a hair follicle (such as from an eyebrow). And they will get a sample of the tissue taken when you had surgery to remove your cancer or when you had a biopsy.

The researchers will use the samples to try to find substances they can measure in the body to help them tell how well the treatment is working. They call these substances biomarkers. And they will use the blood samples to look at your genes. This is to learn more about how genetic changes can lead to cancer and whether certain changes affect how people respond to treatment.

The trial team may also ask your permission to take an extra biopsy during treatment. This is to learn more about what effect the treatment has on the genetic make up of your cancer. If you don’t want to have this extra biopsy, you don’t have to. You can still take part in the trial.

All samples will be stored safely and may be used in the future, but only for research purposes.

You will be asked to fill out a questionnaire before you start treatment, just before the 2nd and 4th cycle of chemotherapy, and every 3 months for a year after you finish treatment. The questionnaire will ask about any side effects you have had and how you have been feeling. This is called a quality of life study.

The trial team will also ask you to fill out a short questionnaire which asks about other members of your family who have had cancer.

People taking part in this trial may also be asked to join extra studies looking at PET scans and MRI scans. Doctors want to find out if these scans can provide more information about bowel cancer with a faulty MSH2 gene.

You may be able to take part in one or both of these studies. Whether or not you are asked to take part will depend on where you are having your treatment and also where in your body the cancer is.

Hospital visits

You will see the doctors and have some tests before you start treatment. The tests include

  • Physical examination
  • Blood tests
  • CT scan
  • Chest X-ray
  • Heart trace (ECG)

You go to hospital twice in each 3 week cycle of treatment. You have regular blood tests. And after 9 weeks of treatment you have a CT scan to check that your cancer has not got any bigger. If the scan shows the cancer has grown, you will stop having the trial treatment and the doctors will discuss other treatment options with you. If the cancer has stayed the same size or got smaller, you will have the next 3 cycles of treatment and then another CT scan.

After you finish treatment you will see the trial doctors and have a CT scan every 3 months for up to 1 year.

If you do take part in the MRI or PET scan study (or both), you will have extra scans

  • Before you start treatment
  • After 2 weeks of treatment
  • When you finish treatment

Having an MRI scan takes about 15 to 30 minutes. If you have PET scans, you have an injection of a small amount of a radioactive drug first. Then you have to wait an hour before having the scan. The scan itself can take up to an hour.

Side effects

The side effects of methotrexate include

There is more information about the side effects of methotrexate on CancerHelp UK.

Location of trial

Top of Form

  • London
  • Sutton

For more information

Please note: we cannot help you to join a specific trial. Unless we state otherwise in this trial summary, you need to print this page and take it to your own doctor to discuss.

Find out how to join a trial or contact our cancer information nurses for other questions about cancer by phone (0808 800 4040), by email, or at

The Information Nurses

Cancer Research UK

Angel Building

407 St John Street


Chief Investigator

Professor David Cunningham

Supported by: Institute of Cancer Research (ICR), The Royal Marsden NHS Foundation Trust

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