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    Lynch Syndrome

    Lynch syndrome is an inherited medical condition in which people affected inherit several genes that make them much more likely to develop certain types of cancer. Most commonly those who have Lynch syndrome are at higher risk for colon, endometrial and ovarian cancer, and are especially likely to get these conditions at a young age, before they turn 45. The condition, which is often diagnosed based on family history or early onset of cancer plus family history, is best fought through examinations that can catch cancer early on when chance of treating it successfully remains highest.

    A person gets this condition by inheritance. When someone has the condition and has children, there is a 50% chance each child may inherit the condition. What you are really inheriting with the condition are some genes that donít perform certain jobs in the body correctly. Some of our genes work to correct DNA that has mistakes in it. People with Lynch syndrome lack the ability for these ďcorrectingĒ genes to work properly, which in time can lead to abnormal tissue growth and cancer.

    If you develop colon, endometrial or ovarian cancer at a young age, and you donít know your family history, you may have inherited this syndrome. If you do know your familyís medical history, there are some guidelines, which establish when to look for the condition. These include history in the family, especially of your mother or father, of developing cancer or tumors, which include the above-mentioned and also cancer of the stomach, kidney, bowel, brain, and skin, and especially whether that history extends to the parentís siblings. Doctors also look for two back-to-back generations of such history of cancer and when cancers were developed, especially if they occurred before the age of 50.

    When doctors know the medical history of family members and Lynch syndrome is suspected, this generally means the condition is treated through earlier screening for cancers. Doctors will also generally refer you to a genetic counselor, who may order genetic testing. Even if you do test positive for the condition, this is not a guarantee that you will get cancer, but you do have a 60-80% chance of developing cancer in your lifetime, hence the extensive screening like colonoscopy, ultrasounds on ovaries, and testing of endometrial tissue, usually yearly once you are in your 30s. A negative test, though, doesnít necessarily mean you donít have Lynch syndrome, so with the condition strongly suspected in your family, you will still need more extensive cancer screening on a yearly basis.

    Greater potential that you have Lynch syndrome may be evaluated by testing any tumors that might develop, to look for the lack of certain proteins in tissue samples. Yet even this testing may not confirm the condition. Given the high rate of inheritance from parents, and the risks of cancers that can be fatal if untreated, even those who test negative for the syndrome are usually followed very closely.

    Many people who have Lynch syndrome are not only physically challenged but also emotionally challenged by the risks of developing cancer. This can be a difficult thing to understand and deal with, and it may be complicated by having lost family members to certain forms of cancer caused by Lynch syndrome. In addition to genetic counseling, many people benefit from regular counseling or contact with support groups to help them deal with the emotional affects arising from the condition.
    Gregory D. Pawelski

    Re: Lynch Syndrome

    The reason some people develop cancer is a growing recognition that a subset of patients carries genetic predispositions for the disease. There is one group of genetically driven cancers that are being encountered in young and middle aged adult patients. One of the best described is the ovarian and breast cancer syndrome associated with the BRCA 1 and 2 genes. BRCA genes may provide therapeutic opportunities with a class of drugs known as PARP inhibitors that target them.

    Another group of patients carry a DNA repair deficiency known as mismatch repair or Lynch Syndrome. People with Lynch Syndrome have an inability to respond to DNA damage. This failure leads to mutational events that can result in cancer. Dr. Robert Nagourney, medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine has learned that the Lynch Syndrome patients may have a similar attribute that can render them hypersensitive to chemotherapeutics. He has one such patient under his care.

    The patient presented with cancer of the uterus. She was managed by a gynecologic oncology service and received a combination of surgery, radiation and chemotherapy. One year later, she revealed recurrent disease in the right, lower abdomen with involvement in the liver. Impending bowel obstruction lead to surgical exploration, providing his laboratory with tissue for analysis.

    When Dr. Nagourney first received the tissue specimen, he was expecting recurrent uterine cancer, the same diagnosis for which she had been treated the year earlier. But, to his surprise, the patient was actually diagnosed with colon cancer. This triggered an analysis of her mismatch repair gene and provided confirmation of Lynch Syndrome.

    What he found amazing was that this patientís colon cancer was sensitive to a two-drug combination that he had never in his career administered for colon cancer. In his previous published work he had consistently identified colon cancer as a bad target for this doublet. Yet, this patientís tumor was sensitive to the combination. Her response was a complete remission within a few months.

    And then, in follow up, her PET/CT revealed a small focus of abnormality, seemingly associated with the colon. With a negative colonoscopy, they waited an additional several months and repeated the study. This time, it was even more evident, there was clearly an abnormality in the left pelvis.

    A biopsy provided an unexpected finding. It was cancer, but it wasnít colon cancer. The patientís original uterine cancer from two years earlier had recurred, most likely as a residual vestige of tumor from an incomplete resection two years before. The drug response profile was distinctly different, but highly consistent with a profile one might find in a patient with mismatch repair.

    As they prepared to treat the patient, she developed gastrointestinal bleeding, a workup for which confirmed erosion by the uterine cancer into the bowel wall. Nagourney decided to use his findings to treat the patient and initiated a three-drug combination. The patientís tolerance was excellent and gastrointestinal bleeding stopped immediately.

    She is now receiving additional courses of therapy and will be evaluated for response in the coming months. The patient is receiving the combination of Irinotecan, Doxil and Cyclophosphamide based upon her specific and unique functional profile of sensitivity. However, each patient is different and it is difficult to extrapolate one patient's effective treatment to another patient. While it is too early to know how well sheíll respond, he is optimistic regarding her outcome. Among the most interesting feature of this and related cases is the fact that the genetic mutation that caused her cancer may be the same genetic mutation that makes it possible to treat her.
    Gregory D. Pawelski


      New Process May Save Lives Of Lynch Syndrome Patients

      People who are at risk for a certain form of colon and other types of cancer may soon have a better chance at surviving or even avoiding the diseases, thanks to a new study done by the Intermountain Clinical Genetics Institute at LDS Hospital.

      The Intermountain Heathcare group of scientists used sophisticated computer modeling to develop a reliable and cost-effective way to identify patients who may have Lynch syndrome, an inherited cancer syndrome that occurs in people who carry a genetic mutation in one of the DNA mismatch repair genes. The mismatch repair (MMR) genes usually help to repair DNA damage that happens to all of us as a part of daily life. But patients who have genetic mutations in these genes have a substantially increased risk of developing colon, uterine, pancreatic and urologic cancers. For some patients, the lifetime risk approaches 80 percent.

      "Being able to identify people who carry a gene change is profoundly important because earlier and more frequent screening - not just for colon cancer, but also for other cancers - could save their lives. It could also save the lives of relatives who have no idea that they may share the increased risk for cancer," says Marc S. Williams, MD, director of the Clinical Genetics Institute at LDS Hospital, and a member of the team that conducted the study, which is published in the August edition of the American Journal of Managed Care.

      A national report on colon cancer a few years ago recommended screening all patients with colon cancer for Lynch syndrome, but stopped short of outlining the best way to do it.

      "There are many tests available that can be used in different combinations to diagnose Lynch syndrome, but there's little clarity about what's the most effective and efficient approach," says James Gudgeon, an analyst with the Clinical Genetics Institute who led the study.

      "Doing full genome sequencing on all colorectal cancer patients would uncover virtually all MMR mutations, but the majority of these patients don't have them. Sequencing costs $4,000 to $6,000 per person, so it would be incredibly costly and inefficient to test everyone."

      The Intermountain team set out to determine if they could develop a system for screening colon cancer patients with existing tests that could keep costs down, but also ensure accurate results. The team gathered information from a variety of sources, including Intermountain patient data, published literature and outside groups to define the best approach to screening. They came up with a plan that relies on two relatively inexpensive tests to eliminate possible Lynch patients before doing full genome sequencing.

      So far, 272 colon cancer patients have been screened according to the group's system, with 261 individuals ruled out as carriers of the abnormal genes.

      "That left only 11 patients who we would recommend going forward with the full genome sequencing test," says Dr. Williams. "That represents the wisest use of the expensive resource of full sequencing."

      The benefits extend not only to the colon cancer patients, but also to members of their extended families, who may also have the MMR mutation.

      "Confirming the Lynch diagnosis changes the way we treat the disease. This form of colon cancer has a generally better prognosis than sporadic colon cancer, but it doesn't respond as well to certain kinds of chemotherapy," says Dr. Williams.

      It can also make patients more alert to other forms of cancer, triggering earlier and more frequent screenings. Some women who are diagnosed with Lynch may choose to have surgery to remove the uterus and ovaries to prevent ovarian or uterine cancer.

      One unusual aspect of the project was the methodology used to carry it out, says Dr. Williams.

      "The team developed customized computer models to examine an assortment of questions that Intermountain decision-makers were interested in. You don't usually see healthcare systems doing this kind of work. We think application of this type of modeling can help healthcare systems make better decisions about how to best treat patients. It can help improve patient outcomes and increase efficiency, which are two of the benefits Intermountain Healthcare is well known for delivering."

      Source: Intermountain Medical Center
      Gregory D. Pawelski


        Aspirin Chemoprevention Recommended in Lynch Syndrome

        Zosia Chustecka
        Medscape Oncology News

        Aspirin chemoprevention in Lynch syndrome should now be a standard of care, say researchers who report that aspirin halved the risk of developing cancer in decade-long trial published online today in the Lancet.

        Lynch syndrome, a hereditary disorder that affects genes involved in DNA repair, predisposes affected individuals to developing cancer at a young age. It affects about 1 person in every 1000, and about half of those affected develop cancer, most commonly colorectal and uterine.

        The finding now being reported was a long time coming; the trial spanned more than a decade. The effect of aspirin was not clear in the first 5 years, but it became "very clear" in the second 5 years, said one of the coauthors, Patrick Morrison, MD, from Queens' University in Belfast, United Kingdom.

        About 15% of the group taking aspirin developed cancer, compared with 30% of those not taking aspirin, he noted.

        The reduction in incidence for colorectal cancer ó the primary end point ó was significant. There was also "substantial protection" against other Lynch-syndrome-associated cancers, (e.g., small intestinal, endometrial, ovarian, kidney), although this did not reach statistical significance.

        "This is a huge breakthrough in terms of cancer prevention," Dr. Morrison said in a statement. "Not only does it show we can reduce cancer rates and ultimately deaths, it opens up other avenues for further cancer prevention research."

        In the future, the team intends to "look at the use of aspirin in the general population as a way of reducing the risk of bowel cancer," he added. This is not currently recommended, mainly because of concerns about toxic effects, according to an accompanying editorial. The editorialists add that this trial, in isolation, does not move that indication any further along.

        However, for the specific population of individuals with Lynch syndrome, the results are "compelling," write editorialists Andrew Chan, MD, from Massachusetts General Hospital in Boston, and Scott Lippman, MD, from the University of Texas M.D. Anderson Cancer Center in Houston. They agree with the study authors on the implications of this research.

        "The results provide a strong rationale for routine use in individuals with Lynch syndrome," the editorialists note.

        First Randomized Trial

        The Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) is the first double-blind randomized trial to study aspirin chemoprevention that has colorectal cancer as the primary end point. It was conducted from 1999 to 2005, and assigned 861 participants in 16 countries to take either aspirin (600 mg daily) or placebo for up to 4 years.

        The first analysis of the trial data, in 2007, showed no difference in the incidence of colorectal cancer between the 2 treatment groups.

        However, by the time another analysis was conducted, in 2010, there had been several more cases of cancer, and a significant difference was seen between the aspirin and placebo groups, with an overall 44% reduced incidence of colorectal cancer.

        When the researchers focused specifically on individuals who had taken aspirin for at least 2 years (about 60% of the group), the difference was even more pronounced, showing a 63% reduction in the incidence of colorectal cancer (10 cases in the aspirin group vs 23 in the placebo group).

        A surprising finding from this study is that although there was a reduction in the incidence of colorectal cancer, there was no difference between the 2 groups in the incidence of polyps, which are precursors to cancer. It appears that the individuals who were taking aspirin still developed polyps, but the polyps did not become cancerous, presumably because of the effects of aspirin.

        Consistent With Previous Data

        "The outcome is consistent with more than 2 decades of observational data showing that the risk of colorectal cancer is halved in regular aspirin consumers," note the authors.

        "Our results, taken in conjunction with recent research, provide a basis for the recommendation of aspirin chemoprevention in Lynch syndrome as a standard of care," said lead author Sir John Burn, MD, FRCOP FRCPCH, FRCOG, FMedSci, professor of clinical genetics at Newcastle University, United Kingdom.

        "We have succeeded in showing the benefits of aspirin because we had a lot of long-term data and because Lynch syndrome is associated with the rapid development of cancer," he said in a statement.

        There might be implications here for the general population, he explained, but "before anyone begins to take aspirin on a regular basis, they should consult their doctor, as aspirin is known to bring with it a risk of stomach complaints, including ulcers." However, "if there is a strong family history of cancer, then people may want to weigh the cost/benefits, particularly because these days drugs that block acid production in the stomach are available over the counter," he added.

        The case for the prescription of aspirin to this high-risk group is clear.

        A summary published in the Lancet asserts that "in the context of the published literature, the trial provides clear evidence that aspirin is an effective chemopreventive agent in hereditary cancer, with an effect equivalent to that achieved with surveillance colonoscopy. The case for the prescription of aspirin to this high-risk group is clear."

        Questions remain about the mechanism of action of the delayed effect that is seen, and therefore about the dose and duration of aspirin to be used, according to the summary. Indirect evidence suggests that a lower dose of aspirin has a similarly protective effect. Another trial (CAPP3, currently recruiting) will compare different doses of aspirin in patients with Lynch syndrome.

        "In the meantime, clinicians should consider the prescription of aspirin for all individuals judged to be at high risk of colorectal cancer, but taking appropriate measures to minimize adverse effects," the summary concludes.

        Dr. Burn reports receiving a speaker's fee from Bayer. His coauthors have disclosed no relevant financial relationships. Dr. Chan reports consulting for Bayer and Millennium. Dr. Lippman has disclosed no relevant financial relationships.

        Lancet.October 27, 2011.
        Gregory D. Pawelski


          Patients with Lynch Syndrome faired better with aspirin use

          By Robert Nagourney, M.D., PhD.
          Rational Therapeutics

          Colorectal cancer is among the leading causes of cancer death in the United States. While most patients develop this disease over a period of decades, associated with an accumulation of genetic mutations (elegantly described by Burt Vogelstein, PhD at Johns Hopkins), a small percentage of patients have a genetic predisposition for this cancer. Among these are those people that carry the familial adenomatous polyp syndrome (FAPS) and those who carry mismatch repair mutations know as Lynch syndrome.

          It is the latter group who are the subject of a report in the October issue of the English journal Lancet. In this study, known as the CAPP2 trial, patients with Lynch syndrome received either placebo or 600mg of aspirin per day (the equivalent of two tablets). The results reveal a statistically significant reduction of colon cancer that clearly favored the aspirin group.

          To put this in perspective, this dramatic improvement in the highest risk population didnít come about as the result of a new signal transduction inhibitor or a monoclonal antibody. Instead, it came from the simple administration of one of mankindís earliest medicinal substances. I applaud these English investigators in conducting this study of 861 patients.

          What is most laudatory is that the intervention, while highly effective, is so inexpensive. In an era of proprietary medications and the promotion of expensive new interventions, it is indeed refreshing to read the results of a well-conducted study using an intervention available to all.

          Data generated more than two decades ago established the benefit of non-steroidal anti-inflammatory drugs like aspirin for the prevention of colorectal cancer. It is gratifying that this simple intervention has additional scientific support both for those with high-risk predisposition, as well as other patients at risk for this relatively common, yet potentially lethal, malignancy.
          Gregory D. Pawelski


            Lynch syndrome: new tales from the crypt

            C. Richard Boland

            GI Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA

            Lynch syndrome is a hereditary disease that predisposes to cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes.1 The disease is inherited in a classic Mendelian dominant way, but tumours act like a recessive diseaseóa somatic mutation is needed to inactivate the uninvolved allele. Individuals with Lynch syndrome are phenotypically normal at birth, but carry a silent germline mutation. At some point in the individual's development, the so-called second hit occurs, which initiates the progression towards neoplasia. In the case of familial adenomatous polyposis, the germline mutation occurs in the APC gene. A somatic mutation in the wild-type APC allele leads to the emergence of a dysplastic aberrant crypt focus, which is a very small adenoma. However, Lynch syndrome is different. The paired mutations do not create a neoplastic phenotype directly, but rather they create a deficiency in DNA MMR, which allows the accumulation of mutations and microsatellite instability.2

            One unanswered question in Lynch syndrome regards what is the timing and sequence of genetic events through which colorectal cancers evolve. One theory is that adenomatous polyps develop as they do in sporadic neoplasia, MMR deficiency occurs within the adenoma, which accelerates the accumulation of mutations, and is followed by step-wise neoplastic progression. An alternative idea is that deficiency of MMR occurs first, and the adenoma evolves from the MMR-deficient cell. Data exist to support either model but no consensus has been reached on which one is most representative. Matthias Kloor and colleagues3 in The Lancet Oncology provide new insights, and show that MMR-deficient crypts can be found in Lynch syndrome before the affected cells seem to be neoplastic. Kloor and colleagues3 did immunohistochemistry for MMR proteins on non-neoplastic colonic tissues that were resected along with colorectal cancer tissue. The investigators identified colonic crypts that were near-normal in appearance and did not express MMR proteins. Moreover, the DNA showed microsatellite instability, suggesting strongly that mismatch repair activity was functionally deficient in these crypts. The absent MMR protein matched the germline mutation, and no MMR-deficient crypts were found in the colons of individuals with sporadic colorectal cancer.

            MMR-deficient crypts are prevalent in colons of patients with Lynch syndrome. About one MMR-deficient crypt was recorded per cm2 of mucosa, or about one per 10 000 crypts in the colon, and slightly fewer were recorded in the small intestine of patients with Lynch syndrome. At least one MMR-deficient crypt was noted in eight of ten colons of patients with Lynch syndrome. Subtle nuclear abnormalities were noted at the bottoms of these crypts, but the architecture was not identifiably neoplastic. MMR-deficient crypts are not the equivalent of dysplastic aberrant crypt foci, which already have a neoplastic phenotype.4 In fact, what happens to all the MMR-deficient crypts is not yet apparent. Unfortunately, these lesions are too small and subtle to be relied upon clinically to suggest a diagnosis of Lynch syndrome. Importantly, the investigators acknowledge that, although they noted these lesions occurred frequently, most patients with Lynch syndrome will develop zero to two cancers, and typically only a few adenomatous polyps, through their lifetimes.5 Small bowel cancers occur in no more than 1ó4% of patients with Lynch syndrome,6 yet that organ has one MMR-deficient crypt per 2 cm2 of mucosa. Obviously, most of these lesions do not develop into cancer. So, what happens to them?

            Kloor and colleagues3 speculate that immunoediting detects and eradicates these lesions because microsatellite instability permits frameshift mutations and predictable types of cancer-associated neoantigens.7, 8 The authors propose that the generation of these neoantigens sensitise the immune system against tumours, and that patients with Lynch syndrome auto-vaccinate themselves against cancer.

            What are the limitations of this work? First, the authors have clearly found MMR-deficient crypts, and the data strongly suggest they are Lynch syndrome-specific, but they did not show that these lesions can grow, are neoplastic, or are precursors to neoplasms. They could be irrelevant to tumour formation. Something restrains or eliminates these lesions, and it might be that MMR-deficient cells simply migrate up the crypt and are eliminated like their MMR-proficient siblings. MMR-deficient crypts do not populate the entire colon, so some mechanism must therefore limit their expansion. In a study,9 MMR-deficiency was uniformly present in adenomatous polyps >9 mm in diameter in Lynch syndrome patients, but was frequently absent in smaller lesions, suggesting that the MMR defect occurs after the evolution of the adenoma in some instances, rather than as a primary event.9

            The authors did not report immune infiltrates in the MMR-deficient crypts, so one might thus anticipate future studies to determine if an immunological reaction exists against these lesions. The missing link in this work is the contrast between the large number of MMR-deficient crypts and the relatively small number of clinically relevant neoplasms in this disease. That said, this work is highly novel, underscores the differences between Lynch syndrome and sporadic colorectal cancers, and raises a fresh group of important questions to be addressed.


            1. Boland CR. Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 2005; 4: 211-218.

            2. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138: 2073-2087.

            3. Kloor M, Huth C, Viogt AY, et al. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol 201210.1016/S1470-2045(12)70109-2.

            4. Gupta AK, Pretlow TP, Schoen RE. Aberrant crypt foci: what we know and what we need to know. Clin Gastroenterol Hepatol 2007; 5: 526-533.

            5. Edelstein DL, Axilbund J, Baxter M, et al. Rapid development of colorectal neoplasia in patients with Lynch syndrome. Clin Gastroenterol Hepatol 2011; 9: 340-343.

            6. Schulmann K, Brasch FE, Kunstmann E, et al. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 2005; 128: 590-599.

            7. Duval A, Hamelin R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 2002; 62: 2447-2454.

            8. Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel DM, Kloor M. Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Fam Cancer 2011; 10: 557-565.

            9. Yurgelun MB, Goel A, Hornick JL, et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res 2012; 5: 574-582.

            The Lancet Oncology, Early Online Publication, 1 May 2012 doi:10.1016/S1470-2045(12)70134-1
            Gregory D. Pawelski


              I have lynch, as does my mother and my 14 year old son. My question is, does Marijuana use effect lynch syndrome?


                There are some serious issues about using marijuana, in any form, if you have a weakened immune system. Tetrahydrocannabinol (THC) is the main psychotropic part of marijuana, an analog of THC is the active ingredient of marinol, a drug frequently given to AIDS patients, among others, for increasing appetite and limiting chemotherapy-induced nausea and vomiting. There is a complicated role marijuana and other cannabinoids play in human health. According to Dr. Jerome E. Groopman, professor of medicine at Harvard Medical School, numerous types of cells display cannabinoid receptors on their outer surfaces, which act as switches that control cellular processes. He has previously demonstrated that THC could have a protective effect against a certain form of invasive, drug-resistant lung cancer. Once a cell is infected, the presence of THC may promote the cellular events that turn it cancerous. THC promotes the production of a viral receptor similar to one that attracts a cell-signalling protein called interleukin-8.

                An international team of immunologists studying the effects of cannabis (including THC) have discovered how smoking marijuana can trigger a suppression of the body's immune functions. The research was published in the European Journal of Immunology. While most immune cells fight against infections and cancers to protect the host, a unique type of immune cell called myeloid-derived suppressor cells (MDSCs) actively suppress the immune system. The presence of these cells is known to increase in cancer patients and it believed that MDSCs may suppress the immune system against cancer therapy, actually promoting cancer growth. These results raise interesting questions on whether increased susceptibility to certain types of cancers caused from smoking marijuana results from induction of MDSCs.
                Gregory D. Pawelski


                  Originally posted by Tamara1229 View Post
                  I have lynch, as does my mother and my 14 year old son. My question is, does Marijuana use effect lynch syndrome?
                  My son is 8 years old. He has developed pretty significant acid reflux and stomach pain over the last 6-8 months. My husband, his dad' died of colon cancer/Lynch's Syndrome. The doctors don't seem concerned about this. I was told he is too young to be tested. How did you get your son tested at age 14? I'm concerned about his symptoms. Thank you Tracy