Recent Progress in Lynch Syndrome: A Patient-Friendly Guide to Familial Colorectal Cancer

Table of Contents

• Key Points
• Introduction: Why This Research Matters
• The Genetic Basis of Lynch Syndrome and Other Familial Colorectal Cancer Syndromes
• Epidemiology: How Common Is Lynch Syndrome?
• Advances in Genetic Testing: From Single-Gene Tests to Multigene Panels
• Colon Surveillance: How Often Should Patients Be Screened?
• Clinical Implications: What This Means for Patients and Families
• Limitations of the Current Research
• Source Information
• Frequently Asked Questions

Key Points

• Lynch syndrome affects about 1 in 279 people; MSH6 and PMS2 mutations are most common but less risky.
• Universal tumor testing for MSI/MMR deficiency is recommended for colorectal or endometrial cancer patients under 70.
• Multigene panel testing finds mutations in 9.9% of unselected colorectal cancer patients, including unexpected BRCA1/2 variants.
• People with Lynch syndrome need colonoscopy every 1–2 years starting at age 20–25 to prevent cancer.
• Immune checkpoint inhibitors like pembrolizumab are approved for MSI-high or MMR-deficient tumors, with dramatic effects in some patients.

Introduction: Why This Research Matters

Doctors 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.

Several landmark discoveries changed everything. First, the gene responsible for FAP—the APC gene—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 microsatellite instability (MSI) 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).

This discovery led directly to the identification of the genes responsible for Lynch syndrome, previously called "hereditary nonpolyposis colorectal cancer" (HNPCC). Lynch syndrome is now known to be caused by mutations in four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. 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.

The Genetic Basis of Lynch Syndrome and Other Familial Colorectal Cancer Syndromes

Today, 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.

Approximately 15-20% of colorectal cancer diagnoses 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 5% of colorectal cancer patients 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."

Lynch syndrome is the most common identifiable form of familial colorectal cancer. It is caused by inherited mutations in four DNA mismatch repair genes—MSH2 (often together with a nearby gene called EPCAM), MLH1, MSH6, and PMS2. People with Lynch syndrome have tumors that nearly always show microsatellite instability (MSI) because their cells can't repair DNA replication errors properly.

Rarely, 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 biallelic mismatch repair deficiency (BMMRD), also known as constitutional mismatch repair deficiency (CMMR-D). These children develop many benign polyps and a wide range of aggressive cancers at a very early age, including brain tumors, leukemias, and lymphomas.

The inherited polyposis syndromes have also been updated. For example, researchers have identified autosomal recessive forms caused by mutations in NTHL1 and MSH3, complementing the previously described MutYH-associated polyposis (MAP). Autosomal dominant forms of oligopolyposis—where people develop fewer than 100 polyps—have been linked to mutations in the POLE and POLD1 genes, which are involved in DNA proofreading. Some patients with serrated polyposis syndrome have been found to carry mutations in a candidate gene called RNF43, 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.

Epidemiology: How Common Is Lynch Syndrome?

Traditionally, 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 3% of colorectal cancer cases and about 2% of endometrial cancer cases. When researchers look at Lynch syndrome patients who were identified because they had cancer, they find that mutations in MLH1 and MSH2 are responsible for the vast majority—between 60% and 80% of cases. MSH6 and PMS2 mutations are less common in this group, and EPCAM mutations (which switch off MSH2) are particularly rare.

But recent population-based research has completely changed that picture. Investigators from the Colon Cancer Family Registry (CCFR) analyzed clinical data from 5,744 people with colorectal cancer and 37,634 of their first-degree relatives—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:

• MLH1 mutations: 0.051% (1 in 1,946 people)
• MSH2 mutations: 0.035% (1 in 2,841 people)
• MSH6 mutations: 0.132% (1 in 758 people)
• PMS2 mutations: 0.140% (1 in 714 people)
• Any MMR gene mutation: 0.359% (1 in 279 people)

These 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 (MSH6 and PMS2) 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.

Founder Mutations and Specific Populations

Lynch 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:

• In Iceland, the overall prevalence of Lynch syndrome is about 0.442% (1 in 226 people). Most cases trace back to three founder mutations: MSH6 p.L585P (carrier frequency 0.080%, or 1 in 1,250), PMS2 p.M1? (0.092%, or 1 in 1,087), and PMS2 p.P246Cfs*3 (0.234%, or 1 in 427).
• In French Canadians, the MSH6 p.Q4* founder mutation is particularly common, with an estimated carrier frequency of 0.249% (1 in 402). Haplotype analysis suggests this mutation arose in a common ancestor between 430 and 656 years ago.
• Among individuals of Ashkenazi Jewish ancestry, founder mutations in MSH2 (c.1906G>C, p.A636P) and MSH6 (c.3959_3962delCAAG and c.3984_3987dupGTCA) appear to account for the majority of Lynch syndrome cases.

Researchers 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.

Biallelic Mismatch Repair Deficiency (BMMRD): A Special Story

Founder mutations also explain a surprisingly large fraction of cases of biallelic MMR deficiency (BMMRD), 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 pediatric-onset brain tumors (like gliomas and medulloblastomas), small bowel and large bowel adenomas and adenocarcinomas, lymphomas, leukemias, and endometrial cancers. Many affected children also have café-au-lait macules (flat, light-brown birthmarks), which can lead to a mistaken diagnosis of neurofibromatosis type 1.

In 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 MSH6 or PMS2, 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.

Advances in Genetic Testing: From Single-Gene Tests to Multigene Panels

The 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 next-generation sequencing (NGS) multigene panels 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.

Studies using multigene panels have consistently shown that a significant number of people who carry pathogenic (disease-causing) mutations do not 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 BRCA1 or BRCA2 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.

Large Studies of Multigene Panel Testing

One large single-center study tested a 25-gene panel in 1,058 colorectal cancer patients who were not preselected based on age, family history, or tumor testing results. The findings:

• 9.9% carried at least one pathogenic germline variant.
• 3.1% had Lynch syndrome (almost all had MSI or defective mismatch repair by IHC).
• 7.0% had at least one non-Lynch mutation, including:
  • 0.8% with adenomatous polyposis (APC or biallelic MutYH mutations)
  • 3.2% with variants linked to modestly increased colorectal cancer risk (the Ashkenazi founder APC p.I1307K allele, monoallelic MutYH variants, or CHEK2 variants)
  • 1.0% with deleterious BRCA1 or BRCA2 variants
  • 1.8% with variants in other genes not known to be linked to colorectal cancer (ATM, CDKN2A, PALB2, and others)

Strikingly, many people with these non-Lynch mutations had no clinical features that suggested their underlying syndrome. For example, 8 of the 11 patients with BRCA1/2 mutations had personal or family histories that did not meet the National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing. Without multigene panel testing, these mutations would have gone completely undiagnosed.

A second, multicenter study examined multigene panel testing in 450 individuals diagnosed with colorectal cancer before age 50. The results were even more striking:

• 16% had a deleterious germline variant.
• 8.2% had Lynch syndrome.
• 2% had an inherited polyposis syndrome (APC, biallelic MutYH, SMAD4).
• 2.2% carried low- or moderate-penetrance colorectal cancer susceptibility genes (APC p.I1307K allele, monoallelic MutYH variants).
• 1.3% had BRCA1/2 mutations.

These data have sparked a major debate: should every 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.

Monogenic Variants of Uncertain Significance

For example, monoallelic MutYH mutations (meaning a person has one altered copy of the MUTYH gene) have been linked to a 1.5- to 2-fold increased risk of colorectal cancer, although they do not 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.

Another 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 pleiotropism, 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 no enrichment of BRCA alterations among familial colorectal cancer cohorts compared to controls, arguing against pleiotropy playing a meaningful role.

Tumor Screening for Lynch Syndrome

Despite the rise of multigene panels, a key finding is that tumor screening with MMR protein IHC and/or MSI testing remains highly effective—with greater than 90% sensitivity—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 70 years old or younger (some experts say all patients, regardless of age).

There are some important caveats:

• For sebaceous neoplasms (skin tumors), sporadic MSI/MMR deficiency appears more common than in other Lynch-associated neoplasms, so results must be interpreted with caution.
• For rectal cancer 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.
• In the real world, abnormal tumor testing doesn't always lead to appropriate genetic counseling and testing. But data increasingly show that somatic NGS panels 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 KRAS, NRAS, and BRAF.

What About Sporadic MSI/MMR-Deficient Tumors?

As 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 somatic hypermethylation of the MLH1 promoter region—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.

A rare caveat is that MLH1 promoter methylation can, in very rare cases, be inherited through non-Mendelian mechanisms, causing a condition called germline MLH1 epimutation, which produces a Lynch-syndrome-like phenotype.

People 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 majority of these patients actually have biallelic somatic inactivation 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 not 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.

Clinical Prediction Models: PREMM5

For 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 PREMM (PREdiction Model for gene Mutations) 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, PREMM5 (available at premm.dfci.harvard.edu), is the first to provide risk assessment for all five Lynch syndrome genes (MSH2+EPCAM, MLH1, MSH6, PMS2).

One 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 ≥5% likelihood of Lynch syndrome. However, the PREMM5 authors advocate using a lower threshold of ≥2.5%, 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.

Colon Surveillance: How Often Should Patients Be Screened?

Multiple guidelines recommend that patients with Lynch syndrome undergo surveillance colonoscopy every 1 to 2 years. 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.

Why 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 within two years. 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.

Clinical Implications: What This Means for Patients and Families

• If you have colorectal cancer or endometrial cancer, ask your doctor whether your tumor has been tested for MSI/MMR deficiency. Universal tumor testing is recommended for all patients under 70 with these cancers—it is the most efficient way to detect Lynch syndrome.
• Families with multiple colorectal cancer cases—especially those diagnosed at younger ages—should seek genetic counseling and consider multigene panel testing. This can uncover Lynch syndrome, polyposis syndromes, and even unexpected gene mutations like BRCA1/2.
• People diagnosed with Lynch syndrome (or those found to carry a mutation without cancer) should have colonoscopy every 1–2 years, starting at age 20–25 (or earlier for certain gene mutations). Regular screening can prevent colorectal cancer by removing polyps before they become malignant.
• Women with Lynch syndrome also need surveillance for endometrial and ovarian cancer, 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.
• Lynch syndrome is inherited in an autosomal dominant 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.
• New immune checkpoint inhibitor therapies (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.

Limitations of the Current Research

This 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.

Second, 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.

Finally, 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.

Frequently Asked Questions

What is Lynch syndrome and why does it increase cancer risk?

Lynch 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.

How common is Lynch syndrome in the general population?

Recent 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.

Who should consider genetic testing for Lynch syndrome?

Ask 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.

What does microsatellite instability (MSI) mean and how is it tested?

MSI 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.

Is there a way to predict Lynch syndrome before cancer develops?

Yes, 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.

What treatments exist for Lynch-related cancers?

Immune 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.

When should a patient with Lynch syndrome or a familial colorectal cancer diagnosis seek a second opinion?

Consider 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.

Source Information

Original article: "Recent Progress in Lynch Syndrome and Other Familial Colorectal Cancer Syndromes"

Authors: 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)

Publication: 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.

This 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.