{"product_id":"recent-progress-in-lynch-syndrome-a-patient-friendly-guide-to-familial-colorectal-cancer","title":"Recent Progress in Lynch Syndrome: A Patient-Friendly Guide to Familial Colorectal Cancer","description":"\u003cp\u003eLynch syndrome, a hereditary condition that dramatically increases the risk of colorectal, endometrial, and other cancers, is far more common and less aggressive than doctors once believed. Recent advances in DNA sequencing have transformed how we detect it, revealing that many patients with Lynch syndrome and other familial colorectal cancer syndromes carry gene mutations that would have been missed by older testing rules. Meanwhile, new immune-boosting therapies are changing the outlook for people with Lynch-related tumors. This review explains the latest science in plain language—from who should get genetic testing to how often patients need colonoscopies.\u003c\/p\u003e\n\n\u003ch1\u003eRecent Progress in Lynch Syndrome: A Patient-Friendly Guide to Familial Colorectal Cancer\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#introduction\"\u003eIntroduction: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#germline-basis\"\u003eThe Genetic Basis of Lynch Syndrome and Other Familial Colorectal Cancer Syndromes\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#epidemiology\"\u003eEpidemiology: How Common Is Lynch Syndrome?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#genetic-testing\"\u003eAdvances in Genetic Testing: From Single-Gene Tests to Multigene Panels\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#colon-surveillance\"\u003eColon Surveillance: How Often Should Patients Be Screened?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications: What This Means for Patients and Families\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Current Research\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#source-information\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eLynch syndrome affects about 1 in 279 people; MSH6 and PMS2 mutations are most common but less risky.\u003c\/li\u003e\n\u003cli\u003eUniversal tumor testing for MSI\/MMR deficiency is recommended for colorectal or endometrial cancer patients under 70.\u003c\/li\u003e\n\u003cli\u003eMultigene panel testing finds mutations in 9.9% of unselected colorectal cancer patients, including unexpected BRCA1\/2 variants.\u003c\/li\u003e\n\u003cli\u003ePeople with Lynch syndrome need colonoscopy every 1–2 years starting at age 20–25 to prevent cancer.\u003c\/li\u003e\n\u003cli\u003eImmune checkpoint inhibitors like pembrolizumab are approved for MSI-high or MMR-deficient tumors, with dramatic effects in some patients.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"introduction\"\u003eIntroduction: Why This Research Matters\u003c\/h2\u003e\n\u003cp\u003eDoctors have known since the early 20th century that colorectal cancer (CRC) can run in families. But it wasn't until the 1990s that researchers began to uncover the underlying biology. Distinctive syndromes like familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome were recognized earlier because of their unique physical signs. But what caused the more common \"non-polyposis\" familial colorectal cancer remained a mystery for decades.\u003c\/p\u003e\n\u003cp\u003eSeveral landmark discoveries changed everything. First, the gene responsible for FAP—the \u003cstrong\u003eAPC gene\u003c\/strong\u003e—was mapped and cloned from chromosome 5q22-23. This opened the door to understanding how most colorectal cancers develop. Then, in 1993, researcher Manuel Perucho and others identified the \u003cstrong\u003emicrosatellite instability (MSI)\u003c\/strong\u003e phenotype—a distinctive genetic fingerprint found in about 15% of colorectal tumors. MSI occurs when the DNA repair system fails, allowing errors to accumulate in short, repeated DNA sequences (microsatellites).\u003c\/p\u003e\n\u003cp\u003eThis discovery led directly to the identification of the genes responsible for \u003cstrong\u003eLynch syndrome\u003c\/strong\u003e, previously called \"hereditary nonpolyposis colorectal cancer\" (HNPCC). Lynch syndrome is now known to be caused by mutations in four DNA mismatch repair (MMR) genes: \u003cstrong\u003eMLH1, MSH2, MSH6, and PMS2\u003c\/strong\u003e. Knowing these genes has revolutionized our understanding of tumor development, cancer natural history, and—most recently—immune-based cancer therapy. This review summarizes the most important progress in Lynch syndrome and related familial colorectal cancer syndromes.\u003c\/p\u003e\n\n\u003ch2 id=\"germline-basis\"\u003eThe Genetic Basis of Lynch Syndrome and Other Familial Colorectal Cancer Syndromes\u003c\/h2\u003e\n\u003cp\u003eToday, researchers can identify the specific gene responsible for nearly every hereditary colorectal cancer syndrome. Still, some families with colorectal cancer clusters have no identifiable germline (inherited) mutation. It has long been known that having a first-degree relative (parent, sibling, or child) with colorectal cancer increases your own risk. Having multiple affected relatives further compounds that risk.\u003c\/p\u003e\n\u003cp\u003eApproximately \u003cstrong\u003e15-20% of colorectal cancer diagnoses\u003c\/strong\u003e occur in people with at least one first-degree relative with the disease. These families are often labeled as having \"familial CRC.\" However, fewer than \u003cstrong\u003e5% of colorectal cancer patients\u003c\/strong\u003e actually harbor a detectable mutation in a known colorectal cancer susceptibility gene. This means that the majority of familial colorectal cancer heritability remains unexplained by single-gene (monogenic) mutations. Polygenic factors, environmental exposures, and behavioral factors likely account for much of this \"missing heritability.\"\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eLynch syndrome\u003c\/strong\u003e is the most common identifiable form of familial colorectal cancer. It is caused by inherited mutations in four DNA mismatch repair genes—\u003cstrong\u003eMSH2 (often together with a nearby gene called EPCAM), MLH1, MSH6, and PMS2\u003c\/strong\u003e. People with Lynch syndrome have tumors that nearly always show microsatellite instability (MSI) because their cells can't repair DNA replication errors properly.\u003c\/p\u003e\n\u003cp\u003eRarely, a person can inherit two mutated copies of the same Lynch syndrome gene—one from each parent. This leads to a devastating childhood condition called \u003cstrong\u003ebiallelic mismatch repair deficiency (BMMRD)\u003c\/strong\u003e, also known as \u003cstrong\u003econstitutional mismatch repair deficiency (CMMR-D)\u003c\/strong\u003e. These children develop many benign polyps and a wide range of aggressive cancers at a very early age, including brain tumors, leukemias, and lymphomas.\u003c\/p\u003e\n\u003cp\u003eThe inherited polyposis syndromes have also been updated. For example, researchers have identified autosomal recessive forms caused by mutations in \u003cstrong\u003eNTHL1\u003c\/strong\u003e and \u003cstrong\u003eMSH3\u003c\/strong\u003e, complementing the previously described \u003cstrong\u003eMutYH-associated polyposis (MAP)\u003c\/strong\u003e. Autosomal dominant forms of oligopolyposis—where people develop fewer than 100 polyps—have been linked to mutations in the \u003cstrong\u003ePOLE\u003c\/strong\u003e and \u003cstrong\u003ePOLD1\u003c\/strong\u003e genes, which are involved in DNA proofreading. Some patients with serrated polyposis syndrome have been found to carry mutations in a candidate gene called \u003cstrong\u003eRNF43\u003c\/strong\u003e, though this condition is usually not familial. Many other putative familial colorectal cancer genes have been proposed, but most are uncommon—sometimes found in only a single family lineage.\u003c\/p\u003e\n\n\u003ch2 id=\"epidemiology\"\u003eEpidemiology: How Common Is Lynch Syndrome?\u003c\/h2\u003e\n\u003cp\u003eTraditionally, the prevalence of Lynch syndrome was calculated by looking at patients already diagnosed with colorectal cancer or endometrial cancer. In that setting, Lynch syndrome accounts for about \u003cstrong\u003e3% of colorectal cancer cases\u003c\/strong\u003e and about \u003cstrong\u003e2% of endometrial cancer cases\u003c\/strong\u003e. When researchers look at Lynch syndrome patients who were identified because they had cancer, they find that mutations in \u003cstrong\u003eMLH1 and MSH2\u003c\/strong\u003e are responsible for the vast majority—between \u003cstrong\u003e60% and 80%\u003c\/strong\u003e of cases. MSH6 and PMS2 mutations are less common in this group, and EPCAM mutations (which switch off MSH2) are particularly rare.\u003c\/p\u003e\n\u003cp\u003eBut recent population-based research has completely changed that picture. Investigators from the \u003cstrong\u003eColon Cancer Family Registry (CCFR)\u003c\/strong\u003e analyzed clinical data from \u003cstrong\u003e5,744 people with colorectal cancer\u003c\/strong\u003e and \u003cstrong\u003e37,634 of their first-degree relatives\u003c\/strong\u003e—all recruited through population-based cancer registries in the United States, Canada, and Australia. Using advanced modeling, they estimated the frequency of disease-causing germline mutations in each of the four MMR genes among the general population:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMLH1\u003c\/strong\u003e mutations: 0.051% (1 in 1,946 people)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMSH2\u003c\/strong\u003e mutations: 0.035% (1 in 2,841 people)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMSH6\u003c\/strong\u003e mutations: 0.132% (1 in 758 people)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePMS2\u003c\/strong\u003e mutations: 0.140% (1 in 714 people)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAny MMR gene\u003c\/strong\u003e mutation: 0.359% (1 in 279 people)\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThese numbers are surprising. They suggest that Lynch syndrome is far more common in the general population than previously thought—affecting roughly 1 in 279 people. Yet the most frequently mutated genes in the general population (\u003cstrong\u003eMSH6 and PMS2\u003c\/strong\u003e) are the ones that show up least often in Lynch patients who have cancer. The best explanation is that MSH6 and PMS2 mutations confer much more modest cancer risks than MLH1 and MSH2 mutations. In other words, many people carrying these variants may never develop cancer.\u003c\/p\u003e\n\u003ch3\u003eFounder Mutations and Specific Populations\u003c\/h3\u003e\n\u003cp\u003eLynch syndrome is found across many ethnicities, but certain populations carry \"founder mutations\"—genetic changes passed down from a common ancestor that make the syndrome especially prevalent in that group. For example:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eIn \u003cstrong\u003eIceland\u003c\/strong\u003e, the overall prevalence of Lynch syndrome is about \u003cstrong\u003e0.442% (1 in 226 people)\u003c\/strong\u003e. Most cases trace back to three founder mutations: \u003cstrong\u003eMSH6 p.L585P\u003c\/strong\u003e (carrier frequency 0.080%, or 1 in 1,250), \u003cstrong\u003ePMS2 p.M1?\u003c\/strong\u003e (0.092%, or 1 in 1,087), and \u003cstrong\u003ePMS2 p.P246Cfs*3\u003c\/strong\u003e (0.234%, or 1 in 427).\u003c\/li\u003e\n  \u003cli\u003eIn \u003cstrong\u003eFrench Canadians\u003c\/strong\u003e, the \u003cstrong\u003eMSH6 p.Q4*\u003c\/strong\u003e founder mutation is particularly common, with an estimated carrier frequency of \u003cstrong\u003e0.249% (1 in 402)\u003c\/strong\u003e. Haplotype analysis suggests this mutation arose in a common ancestor between 430 and 656 years ago.\u003c\/li\u003e\n  \u003cli\u003eAmong individuals of \u003cstrong\u003eAshkenazi Jewish\u003c\/strong\u003e ancestry, founder mutations in \u003cstrong\u003eMSH2\u003c\/strong\u003e (c.1906G\u0026gt;C, p.A636P) and \u003cstrong\u003eMSH6\u003c\/strong\u003e (c.3959_3962delCAAG and c.3984_3987dupGTCA) appear to account for the majority of Lynch syndrome cases.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eResearchers are also identifying candidate founder mutations in other groups, including Americans of German ancestry, African Americans, Latinos, Poles, and others. These findings have important implications for targeted genetic screening in specific communities.\u003c\/p\u003e\n\u003ch3\u003eBiallelic Mismatch Repair Deficiency (BMMRD): A Special Story\u003c\/h3\u003e\n\u003cp\u003eFounder mutations also explain a surprisingly large fraction of cases of \u003cstrong\u003ebiallelic MMR deficiency (BMMRD)\u003c\/strong\u003e, where a child inherits a mutated copy of the same MMR gene from each parent. BMMRD is a rare and often devastating syndrome that causes \u003cstrong\u003epediatric-onset brain tumors\u003c\/strong\u003e (like gliomas and medulloblastomas), \u003cstrong\u003esmall bowel and large bowel adenomas and adenocarcinomas\u003c\/strong\u003e, \u003cstrong\u003elymphomas\u003c\/strong\u003e, \u003cstrong\u003eleukemias\u003c\/strong\u003e, and \u003cstrong\u003eendometrial cancers\u003c\/strong\u003e. Many affected children also have \u003cstrong\u003ecafé-au-lait macules\u003c\/strong\u003e (flat, light-brown birthmarks), which can lead to a mistaken diagnosis of neurofibromatosis type 1.\u003c\/p\u003e\n\u003cp\u003eIn BMMRD, the tumor tissue shows abnormal MMR protein staining (immunohistochemistry, or IHC) even in normal tissue, but—curiously—the cancers often do not show MSI by polymerase chain reaction (PCR) testing. Of the small number of reported cases, a surprisingly high proportion involve biallelic mutations in \u003cstrong\u003eMSH6 or PMS2\u003c\/strong\u003e, likely because these mutations are more common in the general population. Another puzzling feature is that family members of BMMRD patients—who by definition have Lynch syndrome—seem to have relatively few Lynch-related cancers. Again, this may reflect that MSH6 and PMS2 mutations have lower penetrance (i.e., they cause cancer less often) than MLH1 or MSH2 mutations.\u003c\/p\u003e\n\n\u003ch2 id=\"genetic-testing\"\u003eAdvances in Genetic Testing: From Single-Gene Tests to Multigene Panels\u003c\/h2\u003e\n\u003cp\u003eThe past decade has seen a dramatic transformation in how doctors evaluate people with suspected hereditary cancer risk. Instead of testing one gene at a time, many clinics now use \u003cstrong\u003enext-generation sequencing (NGS) multigene panels\u003c\/strong\u003e that analyze dozens of cancer susceptibility genes simultaneously. These panels are commercially available and often include genes with a wide range of cancer risks—many of which are still poorly understood.\u003c\/p\u003e\n\u003cp\u003eStudies using multigene panels have consistently shown that a significant number of people who carry pathogenic (disease-causing) mutations do \u003cstrong\u003enot\u003c\/strong\u003e fit the traditional syndrome-specific guidelines. For example, some Lynch syndrome patients don't meet the old \"Amsterdam Criteria\" or \"Bethesda Guidelines.\" Others have atypical patterns—such as colorectal cancer patients with \u003cstrong\u003eBRCA1 or BRCA2\u003c\/strong\u003e mutations (the genes best known for breast and ovarian cancer), or breast cancer patients with Lynch syndrome mutations. Some rare individuals carry mutations in both Lynch and non-Lynch genes at the same time.\u003c\/p\u003e\n\u003ch3\u003eLarge Studies of Multigene Panel Testing\u003c\/h3\u003e\n\u003cp\u003eOne large single-center study tested a 25-gene panel in \u003cstrong\u003e1,058 colorectal cancer patients\u003c\/strong\u003e who were not preselected based on age, family history, or tumor testing results. The findings:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e9.9%\u003c\/strong\u003e carried at least one pathogenic germline variant.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e3.1%\u003c\/strong\u003e had Lynch syndrome (almost all had MSI or defective mismatch repair by IHC).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e7.0%\u003c\/strong\u003e had at least one \u003cem\u003enon\u003c\/em\u003e-Lynch mutation, including:\n    \u003cul\u003e\n      \u003cli\u003e0.8% with adenomatous polyposis (APC or biallelic MutYH mutations)\u003c\/li\u003e\n      \u003cli\u003e3.2% with variants linked to modestly increased colorectal cancer risk (the Ashkenazi founder APC p.I1307K allele, monoallelic MutYH variants, or CHEK2 variants)\u003c\/li\u003e\n      \u003cli\u003e1.0% with deleterious BRCA1 or BRCA2 variants\u003c\/li\u003e\n      \u003cli\u003e1.8% with variants in other genes not known to be linked to colorectal cancer (ATM, CDKN2A, PALB2, and others)\u003c\/li\u003e\n    \u003c\/ul\u003e\n  \u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eStrikingly, many people with these non-Lynch mutations had no clinical features that suggested their underlying syndrome. For example, \u003cstrong\u003e8 of the 11 patients with BRCA1\/2 mutations\u003c\/strong\u003e had personal or family histories that did \u003cem\u003enot\u003c\/em\u003e meet the National Comprehensive Cancer Network (NCCN) criteria for BRCA1\/2 testing. Without multigene panel testing, these mutations would have gone completely undiagnosed.\u003c\/p\u003e\n\u003cp\u003eA second, multicenter study examined multigene panel testing in \u003cstrong\u003e450 individuals diagnosed with colorectal cancer before age 50\u003c\/strong\u003e. The results were even more striking:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e16%\u003c\/strong\u003e had a deleterious germline variant.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e8.2%\u003c\/strong\u003e had Lynch syndrome.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e2%\u003c\/strong\u003e had an inherited polyposis syndrome (APC, biallelic MutYH, SMAD4).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e2.2%\u003c\/strong\u003e carried low- or moderate-penetrance colorectal cancer susceptibility genes (APC p.I1307K allele, monoallelic MutYH variants).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e1.3%\u003c\/strong\u003e had BRCA1\/2 mutations.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThese data have sparked a major debate: should \u003cem\u003eevery\u003c\/em\u003e person diagnosed with colorectal cancer—or at least every patient diagnosed before age 50—undergo multigene panel testing, regardless of family history or tumor testing? The counterargument is that for many \"unexpected\" germline mutations, we still don't know the exact cancer risk or how best to manage it. This is especially true for genes that appear to only modestly increase risk, which seem to be quite common in the population.\u003c\/p\u003e\n\u003ch3\u003eMonogenic Variants of Uncertain Significance\u003c\/h3\u003e\n\u003cp\u003eFor example, \u003cstrong\u003emonoallelic MutYH mutations\u003c\/strong\u003e (meaning a person has one altered copy of the \u003cem\u003eMUTYH\u003c\/em\u003e gene) have been linked to a \u003cstrong\u003e1.5- to 2-fold increased risk of colorectal cancer\u003c\/strong\u003e, although they do \u003cem\u003enot\u003c\/em\u003e cause polyposis (that requires two mutated copies, as in MAP). Based on this evidence, the NCCN now recommends earlier and more frequent colonoscopy screening for monoallelic MutYH carriers, even without a family history—although it remains unknown whether this actually improves survival.\u003c\/p\u003e\n\u003cp\u003eAnother area of controversy involves finding high-penetrance mutations in genes not traditionally linked to colorectal cancer—like BRCA1 or BRCA2—when someone is diagnosed with colorectal cancer. Some experts argue these are simply background population mutations detected by \"screening\" everyone. Others suggest \u003cstrong\u003epleiotropism\u003c\/strong\u003e, where a single gene mutation causes multiple different clinical features, may explain a weak link between BRCA mutations and some colorectal cancers. So far, however, studies have found \u003cem\u003eno enrichment\u003c\/em\u003e of BRCA alterations among familial colorectal cancer cohorts compared to controls, arguing against pleiotropy playing a meaningful role.\u003c\/p\u003e\n\u003ch3\u003eTumor Screening for Lynch Syndrome\u003c\/h3\u003e\n\u003cp\u003eDespite the rise of multigene panels, a key finding is that \u003cstrong\u003etumor screening with MMR protein IHC and\/or MSI testing remains highly effective\u003c\/strong\u003e—with greater than \u003cstrong\u003e90% sensitivity\u003c\/strong\u003e—for identifying Lynch syndrome among people with colorectal or endometrial cancer. Current guidelines still recommend this type of universal tumor testing for all people with colorectal or endometrial cancer who are \u003cstrong\u003e70 years old or younger\u003c\/strong\u003e (some experts say all patients, regardless of age).\u003c\/p\u003e\n\u003cp\u003eThere are some important caveats:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eFor \u003cstrong\u003esebaceous neoplasms\u003c\/strong\u003e (skin tumors), sporadic MSI\/MMR deficiency appears more common than in other Lynch-associated neoplasms, so results must be interpreted with caution.\u003c\/li\u003e\n  \u003cli\u003eFor \u003cstrong\u003erectal cancer\u003c\/strong\u003e that has been treated with radiation before surgery, MMR IHC can be inaccurate—mainly because radiation causes artefactual loss of MSH6 in the surgical specimen. In this situation, testing the pre-treatment biopsy or using PCR-based MSI testing is preferred.\u003c\/li\u003e\n  \u003cli\u003eIn the real world, abnormal tumor testing doesn't always lead to appropriate genetic counseling and testing. But data increasingly show that \u003cstrong\u003esomatic NGS panels\u003c\/strong\u003e can assess mutation burden as a highly concordant surrogate for MSI\/dMMR status. This means that a single tumor NGS test could potentially replace traditional MMR IHC and MSI testing in the future, especially when doctors are also looking for other clinically relevant mutations like \u003cstrong\u003eKRAS, NRAS, and BRAF\u003c\/strong\u003e.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003ch3\u003eWhat About Sporadic MSI\/MMR-Deficient Tumors?\u003c\/h3\u003e\n\u003cp\u003eAs universal tumor testing has grown, doctors have discovered that not all MSI\/MMR-deficient tumors are caused by Lynch syndrome. The most common cause is \u003cstrong\u003esomatic hypermethylation of the MLH1 promoter region\u003c\/strong\u003e—a chemical change that turns off the MLH1 gene in the tumor only, not the whole body. Testing for this methylation is routinely used to decide which patients can skip germline testing for Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eA rare caveat is that \u003cstrong\u003eMLH1 promoter methylation\u003c\/strong\u003e can, in very rare cases, be inherited through non-Mendelian mechanisms, causing a condition called \u003cstrong\u003egermline MLH1 epimutation\u003c\/strong\u003e, which produces a Lynch-syndrome-like phenotype.\u003c\/p\u003e\n\u003cp\u003ePeople with MSI\/MMR-deficient tumors who have no germline Lynch mutation and no MLH1 hypermethylation were once said to have \"presumed Lynch syndrome\" or \"Lynch-like syndrome.\" But recent somatic NGS studies have shown that the \u003cem\u003emajority\u003c\/em\u003e of these patients actually have \u003cstrong\u003ebiallelic somatic inactivation\u003c\/strong\u003e of one or more MMR genes within their tumors. In other words, the two mutation \"hits\" happened in the tumor tissue itself, not through inheritance—so these individuals do \u003cem\u003enot\u003c\/em\u003e have Lynch syndrome. Unfortunately, clinical testing for biallelic somatic inactivation is not widely available, and insurance may not cover it if germline Lynch syndrome testing has already been done.\u003c\/p\u003e\n\u003ch3\u003eClinical Prediction Models: PREMM5\u003c\/h3\u003e\n\u003cp\u003eFor people who have not had cancer and therefore have no tumor tissue to test, or when tumor testing is normal but clinical suspicion remains high, clinical prediction models are an accurate and cost-effective way to identify who might benefit from germline testing. The \u003cstrong\u003ePREMM (PREdiction Model for gene Mutations)\u003c\/strong\u003e models look at a person's sex, age, and personal\/family history of cancer to generate a numeric estimate of the likelihood of Lynch syndrome. The newest version, \u003cstrong\u003ePREMM5\u003c\/strong\u003e (available at \u003ca href=\"http:\/\/premm.dfci.harvard.edu\"\u003epremm.dfci.harvard.edu\u003c\/a\u003e), is the first to provide risk assessment for all five Lynch syndrome genes (MSH2+EPCAM, MLH1, MSH6, PMS2).\u003c\/p\u003e\n\u003cp\u003eOne limitation is that PREMM5's ability to identify PMS2 mutation carriers is suboptimal, because many PMS2 families have a milder (attenuated) cancer history. Current NCCN guidelines recommend genetic evaluation when PREMM5 predicts a \u003cstrong\u003e≥5% likelihood\u003c\/strong\u003e of Lynch syndrome. However, the PREMM5 authors advocate using a lower threshold of \u003cstrong\u003e≥2.5%\u003c\/strong\u003e, because this dramatically improves sensitivity—meaning fewer carriers are missed. Encouragingly, recent implementation studies show that PREMM5 can be successfully incorporated into routine gastroenterology clinics, raising hope that widespread risk assessment before cancer develops could soon become standard practice.\u003c\/p\u003e\n\n\u003ch2 id=\"colon-surveillance\"\u003eColon Surveillance: How Often Should Patients Be Screened?\u003c\/h2\u003e\n\u003cp\u003eMultiple guidelines recommend that patients with Lynch syndrome undergo \u003cstrong\u003esurveillance colonoscopy every 1 to 2 years\u003c\/strong\u003e. For non-Lynch patients at increased risk for colorectal cancer (for example, those with a family history but no identifiable mutation), the recommended interval is usually every five years, depending on the situation.\u003c\/p\u003e\n\u003cp\u003eWhy are Lynch syndrome patients screened so much more often? Because even after a colonoscopy that appears to clear all adenomas, some Lynch syndrome patients develop new neoplastic lesions \u003cstrong\u003ewithin two years\u003c\/strong\u003e. This rapid growth rate means that a five-year screen would be far too late. Frequent surveillance with removal of any polyps found significantly reduces the risk of colorectal cancer in Lynch syndrome.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eClinical Implications: What This Means for Patients and Families\u003c\/h2\u003e\n\u003cul\u003e\n  \u003cli\u003eIf you have colorectal cancer or endometrial cancer, ask your doctor whether your tumor has been tested for \u003cstrong\u003eMSI\/MMR deficiency\u003c\/strong\u003e. Universal tumor testing is recommended for all patients under 70 with these cancers—it is the most efficient way to detect Lynch syndrome.\u003c\/li\u003e\n  \u003cli\u003eFamilies with multiple colorectal cancer cases—especially those diagnosed at younger ages—should seek \u003cstrong\u003egenetic counseling\u003c\/strong\u003e and consider multigene panel testing. This can uncover Lynch syndrome, polyposis syndromes, and even unexpected gene mutations like BRCA1\/2.\u003c\/li\u003e\n  \u003cli\u003ePeople diagnosed with Lynch syndrome (or those found to carry a mutation without cancer) should have \u003cstrong\u003ecolonoscopy every 1–2 years\u003c\/strong\u003e, starting at age 20–25 (or earlier for certain gene mutations). Regular screening can prevent colorectal cancer by removing polyps before they become malignant.\u003c\/li\u003e\n  \u003cli\u003eWomen with Lynch syndrome also need \u003cstrong\u003esurveillance for endometrial and ovarian cancer\u003c\/strong\u003e, often including annual pelvic exams, ultrasound, and endometrial biopsy. In some cases, risk-reducing hysterectomy and salpingo-oophorectomy may be an option to discuss with their care team.\u003c\/li\u003e\n  \u003cli\u003eLynch syndrome is inherited in an \u003cstrong\u003eautosomal dominant\u003c\/strong\u003e pattern. If you carry a mutation, each of your children has a 50% chance of inheriting it. Genetic testing of at-risk relatives can allow them to take preventive steps before cancer ever occurs.\u003c\/li\u003e\n  \u003cli\u003eNew \u003cstrong\u003eimmune checkpoint inhibitor therapies\u003c\/strong\u003e (such as pembrolizumab) have been approved for MSI-high or mismatch repair-deficient tumors, including many Lynch-related cancers. Because these tumors have thousands of mutations, they are highly visible to the immune system, and immune therapy can be dramatically effective.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Current Research\u003c\/h2\u003e\n\u003cp\u003eThis review article summarizes existing research, but several important limitations remain. First, the true cancer risks associated with many “unexpected” germline mutations found by multigene panels are not yet well defined—especially for genes that appear to confer only a modestly increased risk.\u003c\/p\u003e\n\u003cp\u003eSecond, the population prevalence estimates for Lynch syndrome were based on modeling from the Colon Cancer Family Registry, which may not perfectly represent all ethnic and racial groups. Third, the PREMM5 model has suboptimal accuracy for PMS2 mutation carriers, meaning some at-risk people may still be missed. Fourth, testing for biallelic somatic MMR inactivation—which would rule out Lynch syndrome in many patients with MSI\/MMR-deficient tumors—is not yet widely available or covered by insurance.\u003c\/p\u003e\n\u003cp\u003eFinally, although immune checkpoint inhibitors have transformed treatment for advanced MSI-high cancers, not all patients respond, and the long-term outcomes are still being studied.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is Lynch syndrome and why does it increase cancer risk?\u003c\/h3\u003e\n\u003cp\u003eLynch syndrome is an inherited condition caused by mutations in DNA mismatch repair genes like MLH1, MSH2, MSH6, and PMS2. These genes normally fix DNA replication errors. When faulty, errors build up in microsatellites, causing microsatellite instability and greatly increasing risks of colorectal, endometrial, and other cancers.\u003c\/p\u003e\n\u003ch3\u003eHow common is Lynch syndrome in the general population?\u003c\/h3\u003e\n\u003cp\u003eRecent population-based modeling from the Colon Cancer Family Registry suggests that about 1 in 279 people carry a mutation in one of the four Lynch syndrome genes. The most common mutations are in MSH6 and PMS2, but these confer lower cancer risks than MLH1 and MSH2 mutations.\u003c\/p\u003e\n\u003ch3\u003eWho should consider genetic testing for Lynch syndrome?\u003c\/h3\u003e\n\u003cp\u003eAsk your doctor about testing if you have colorectal or endometrial cancer, especially before age 70, or if you have multiple relatives with colorectal cancer. Multigene panel testing can detect mutations even when you don't meet traditional criteria like the Amsterdam or Bethesda guidelines.\u003c\/p\u003e\n\u003ch3\u003eWhat does microsatellite instability (MSI) mean and how is it tested?\u003c\/h3\u003e\n\u003cp\u003eMSI is a genetic fingerprint seen in about 15% of colorectal tumors when DNA repair fails. Tumors are screened using MMR protein immunohistochemistry or MSI testing, which have greater than 90% sensitivity for Lynch syndrome. This is recommended for all colorectal or endometrial cancers in people 70 or younger.\u003c\/p\u003e\n\u003ch3\u003eIs there a way to predict Lynch syndrome before cancer develops?\u003c\/h3\u003e\n\u003cp\u003eYes, clinical prediction models like PREMM5 estimate the likelihood of Lynch syndrome based on sex, age, and personal or family cancer history. PREMM5 covers all five Lynch genes. A score of 2.5% or higher suggests genetic evaluation, and it is now being used in gastroenterology clinics.\u003c\/p\u003e\n\u003ch3\u003eWhat treatments exist for Lynch-related cancers?\u003c\/h3\u003e\n\u003cp\u003eImmune checkpoint inhibitor therapies, such as pembrolizumab, are approved for MSI-high or mismatch repair-deficient tumors, including many Lynch-related cancers. Because these tumors have thousands of mutations, they are highly visible to the immune system, making immune therapy potentially dramatically effective, though not all patients respond.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with Lynch syndrome or a familial colorectal cancer diagnosis seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eConsider a second opinion if genetic testing reveals an unexpected mutation, such as a BRCA1\/2 variant in a colorectal cancer patient, because multigene panels often find mutations outside traditional Lynch syndrome guidelines. Also seek one if tumor MSI\/MMR testing is abnormal but germline testing is normal, since this may reflect somatic alterations rather than inherited Lynch syndrome. Before deciding on screening, remember that Lynch syndrome patients need colonoscopy every 1 to 2 years, starting at age 20–25. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source-information\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article:\u003c\/strong\u003e \"Recent Progress in Lynch Syndrome and Other Familial Colorectal Cancer Syndromes\"\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Patrick M. Boland, M.D. (Roswell Park Cancer Institute, Buffalo, NY), Matthew B. Yurgelun, M.D. (Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA), and C. Richard Boland, M.D. (UCSD School of Medicine, San Diego, CA)\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e CA: A Cancer Journal for Clinicians, 2018 May; 68(3): 217–231. doi:10.3322\/caac.21448. Author manuscript available in PMC 2019 May 01.\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research published in a leading oncology journal. It is intended for educational purposes and does not replace individualized medical advice. Patients with concerns about hereditary cancer risk should consult their healthcare providers and a certified genetic counselor.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47461162877084,"sku":null,"price":0.0,"currency_code":"EUR","in_stock":true}],"url":"https:\/\/diagnosticdetectives.sg\/products\/recent-progress-in-lynch-syndrome-a-patient-friendly-guide-to-familial-colorectal-cancer","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}