Lynch Syndrome

Lynch Syndrome (LS) is a hereditary cancer predisposition syndrome characterized by an increased lifetime chance of acquiring malignancies, especially colorectal and endometrial. These tumors have microsatellite instability (MSI) due to flaws in the cellular mismatch repair (MMR) system, which is a method by which cells repair unpaired and/or mismatched DNA fragments, resulting in increased cellular proliferation. For the uninitiated, cancer.org defines ‘MSI’ as ‘a change that occurs in certain cells (such as cancer cells) in which the number of repeated DNA bases in a microsatellite (a short, repeated sequence of DNA) is different from what it was when the microsatellite was inherited.’

LS is linked to a variety of cancers, including gastrointestinal (GI) (e.g., gastric, small intestine, hepatobiliary, and pancreatic) and extra-GI (e.g., prostate, ovaries, skin, central nervous system, and upper urinary tract). LS has an autosomal dominant inheritance pattern, with germline pathogenic mutations in one of the MMR genes that, in health, preserve genomic stability. In the United Kingdom, an estimated 1/450 persons suffer from LS, with just 5% being diagnosed. 

The lifetime risk of colorectal cancer (CRC) in LS individuals ranges from 10-80%, depending on the MMR mutation and age, and it is considered to account for 3-5% of all CRCs. This makes LS one of the most common cancer susceptibility disorders.

Some families have several relatives with colon cancer or other types of cancer. These malignancies could be caused by Lynch syndrome. Lynch syndrome dramatically raises your risk of having colon cancer, which often occurs before the age of 45. It causes about 3% of all colon cancers and may also increase the risk of other malignancies, including endometrial and ovarian cancer in women.

The good news is that major medical institutes offer genetic screening and testing, which discovers Lynch syndrome in an estimated 95% of people. By determining whether you or your family members have Lynch syndrome, you can take steps to seek proper medical care and monitoring, such as regular and consistent colonoscopies and check-ups. This can help diagnose and prevent cancer, thereby saving precious lives.

Executive Summary

  • Esophageal cancer is a relatively rare but serious form of cancer that affects the tube connecting the throat to the stomach. There are two main types: squamous cell carcinoma (SCC) and adenocarcinoma (AC), with AC becoming more common in the US in recent years. The disease is often diagnosed at later stages due to lack of early symptoms, resulting in a poor overall survival rate.

  • Several factors can increase the risk of developing esophageal cancer, including tobacco use, heavy alcohol consumption, obesity, and chronic acid reflux leading to a condition called Barrett's esophagus. Other risk factors include poor diet, certain genetic factors, and exposure to certain chemicals or environmental pollutants. Many of these risk factors are modifiable, but some are associated with lower socioeconomic status, making changes difficult for some populations.

  • Diagnosis of esophageal cancer typically involves a combination of endoscopy, biopsy, and imaging tests like CT or PET scans. Common symptoms include difficulty swallowing, unexplained weight loss, chronic indigestion, chest pain, and sometimes hoarseness or coughing. Unfortunately, these symptoms often don't appear until the cancer is in more advanced stages, highlighting the importance of regular check-ups for those at higher risk.

  • Treatment for esophageal cancer depends on the stage of the disease and the patient's overall health. For early-stage cancers, surgery to remove the affected part of the esophagus may be an option. More advanced cases often require a combination of chemotherapy, radiation therapy, and sometimes targeted therapies or immunotherapy. In cases where the cancer cannot be surgically removed, treatments focus on reducing symptoms and improving quality of life.

  • Esophageal cancer presents significant challenges due to its often late diagnosis and the complex nature of treatments. Surgery, when possible, can be difficult and recovery can take up to two years or more. The overall five-year survival rate is low, but outcomes are better when the cancer is caught early. Ongoing research is exploring new treatment options, including targeted therapies and immunotherapies, which may improve outcomes in the future.

  • Supportive care, including palliative care, plays a crucial role in managing esophageal cancer. This approach focuses on improving quality of life by managing symptoms, providing nutritional support, and addressing psychological and social needs. Some research is also exploring the potential benefits of integrative therapies, such as certain herbal compounds or nutritional interventions, in supporting conventional treatments. However, patients should always discuss any complementary treatments with their healthcare team.

Genetics of Lynch Syndrome

Lynch syndrome is caused by inherited alterations (mutations) in genes that influence DNA mismatch repair, a process that corrects errors created during DNA replication. These genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) often protect you from some malignancies, however, some mutations prevent them from operating properly.

Everyone carries two copies of each gene involved in Lynch Syndrome, one from their mother and one from their father. Even if a person inherits a Lynch syndrome gene mutation, they retain the normal copy from their other parent. Cancer begins when a second mutation damages the normal working copy of the gene so that the person no longer has a copy of the gene that operates correctly. Unlike the inherited Lynch syndrome mutation, the second mutation would not be prevalent throughout the person’s body, but would only be present in the cancer tissue. However, not everyone with Lynch syndrome develops cancer.

Colorectal cancer can be caused by mutations in genes other than those associated with Lynch syndrome. This indicates that not all colorectal cancer families will have Lynch syndrome gene mutations. These mutations could be detected through genetic testing with multigene panels, which screen for mutations in multiple genes at the same time.

MLH1 gene

The MLH1 gene encodes a protein necessary for DNA repair. This protein aids in the correction of errors made during DNA replication, which occurs prior to cell division. The MLH1 protein associates with another protein, PMS2, to form a dimer, or two-protein complex. This complex coordinates the activity of other proteins that correct faults made during DNA replication. Repairs are performed by deleting a portion of DNA that contains errors and replacing it with a correct DNA sequence. The MLH1 gene is part of a group of genes known as mismatch repair (MMR). The MLH1 protein can form a dimer with the MLH3 or PMS1 protein; however, the function of these dimers is unclear.

The MLH1 gene variations involved in this syndrome either preclude the creation of the MLH1 protein from one copy of the gene or result in an altered version of the protein that does not function normally. A decrease in the functional MLH1 protein causes an increase in unrepaired DNA mistakes during cell division. As the cells proliferate, the mistakes accumulate, potentially causing aberrant cell function and raising the likelihood of tumor growth in the colon or elsewhere in the body.

Because some functional MLH1 protein is made from the normal copy of the gene, mismatch repair activity in Lynch syndrome is diminished but not eliminated. This disparity in DNA repair activity levels probably explains why malignancies in Lynch syndrome commonly occur in adults.

MSH2 gene

The MSH2 gene encodes a protein that is necessary for DNA repair. This protein aids in the correction of errors made during DNA replication, which occurs prior to cell division. To create a two-protein complex known as a dimer, the MSH2 protein combines with one of two additional proteins, MSH6 or MSH3 (produced by distinct genes). This complex recognizes DNA mistakes that occur during replication. Another group of proteins, the MLH1-PMS2 dimer, then binds to the MSH2 dimer and corrects the faults by deleting mismatched DNA and replicating a new section. MSH2 is one of the mismatch repair (MMR) genes.

MSH2 gene variations associated with Lynch syndrome can result in the creation of an unusually short or inactive MSH2 protein, as well as the inability to produce any protein from one copy of the gene. A changed protein is unable to execute its regular function. A decrease in the functional MSH2 protein causes an increase in unrepaired DNA mistakes during cell division. Errors accumulate as cells divide, increasing the chance of tumor growth in the colon or elsewhere in the body.

EPCAM gene

The EPCAM gene encodes a protein called epithelial cellular adhesion molecule (EpCAM). This protein is found in epithelial cells, which line the body's surfaces and cavities. The EpCAM protein is present in the membrane that surrounds epithelial cells, where it helps cells adhere to one another. Furthermore, the protein in the cell membrane can be broken at a certain position, releasing a fragment known as the intracellular domain (EpICD), which aids in signaling from outside the cell to the cell's nucleus.

Certain polymorphisms (also known as mutations) in the EPCAM gene are linked to Lynch syndrome, a condition that raises the risk of developing a variety of malignancies, particularly those of the large intestine (colon) and the rectum (together known as colorectal cancer). These variations are responsible for up to 3 percent of Lynch syndrome patients. On chromosome 2, the EPCAM gene is located adjacent to another gene known as MSH2. Each gene encodes instructions for producing a specific messenger RNA (mRNA), which acts as the protein's genetic blueprint. The Lynch syndrome EPCAM gene variations eliminate a region that indicates the gene's end, resulting in the creation of a lengthy mRNA including both EPCAM and MSH2.

For unexplained causes, these EPCAM gene variations turn off (inactivate) the MSH2 gene via a mechanism known as promoter hypermethylation. The promoter is a DNA region near the start of the gene that regulates gene activity (expression). Hypermethylation happens when too many tiny molecules known as methyl groups are linked to the promoter region. The additional methyl groups on the MSH2 promoter limit the expression of the MSH2 gene, resulting in reduced protein production in epithelial cells.

MSH6 gene

The MSH6 gene encodes a protein that is necessary for DNA repair. This protein aids in the correction of errors made during DNA replication, which occurs prior to cell division. The MSH6 protein interacts with another protein named MSH2 (produced by the MSH2 gene) to form a two-protein complex known as a dimer. This complex recognizes DNA mistakes that occur during replication. Additional proteins, including the MLH1-PMS2 dimer, subsequently correct the faults by deleting the mismatched DNA and reproducing a new section. The MSH6 gene is part of a group of genes known as mismatch repair (MMR).

MSH6 gene variations associated with this disorder result in the creation of an unusually short, nonfunctional MSH6 protein, a partially active form of the protein, or no protein product from one copy of the gene. A decrease in the functional MSH6 protein causes an increase in unrepaired DNA mistakes during cell division. As the cells proliferate, the mistakes accumulate, potentially causing aberrant cell function and raising the likelihood of tumor growth in the colon or elsewhere in the body. Because there is some functional MSH6 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent.

PMS2 gene

The PMS2 gene encodes a protein that is necessary for DNA repair. This protein aids in the correction of errors made during DNA replication, which occurs prior to cell division. The PMS2 protein combines with another protein called MLH1 (derived from the MLH1 gene) to form a two-protein complex known as a dimer. This complex coordinates the activity of other proteins that correct faults made during DNA replication. Repairs are done by deleting the error-containing segment of DNA and replacing it with a repaired DNA sequence. The PMS2 gene belongs to a group of genes known as mismatch repair (MMR) genes.

PMS2 gene variations associated in this disorder produce an unusually short or inactive PMS2 protein from a single copy of the gene. The changed protein is unable to effectively repair mistakes made during DNA replication. Errors accumulate as cells divide, increasing the chance of tumor growth in the colon or elsewhere in the body. Because some functional PMS2 protein is made from the normal copy of the gene, mismatch repair activity in Lynch syndrome is diminished but not eliminated.

Clinical Manifestations

Types of cancers associated with Lynch Syndrome

Colorectal cancer

Lynch syndrome patients are more likely to develop colorectal cancer (CRC), as well as cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate.

The probability of getting CRC is much higher for MLH1 and MHS2 pathogenic variants compared to MSH6 or PMS2 pathogenic variants. Individuals with MSH6 and PMS2 pathogenic variants have older average ages at the beginning of CRC diagnosis than those with MLH1 and MSH2 pathogenic variants: 42-69 years for MSH6 and 61-66 years for PMS2, compared to 44 years for MLH1 and MSH2. These findings explain why CRC screening in people with an MLH1 or MSH2 pathogenic variant should begin earlier than in people with an MSH6 or PMS2 pathogenic variant, unless family history indicates otherwise. 

Ovarian cancer

Females with a germline MLH1, MSH2, or MSH6 pathogenic mutation have an 11%-17% probability of developing ovarian cancer by the age of 70. Risk estimates derived from cohort studies are quite variable. Females with a germline PMS2 pathogenic mutation have a relatively low increased risk of developing ovarian cancer. Lynch syndrome-associated ovarian cancer is diagnosed at an average age of 43 to 46 years. The majority of Lynch syndrome-associated ovarian tumors are of the endometrioid histologic type. Borderline ovarian tumors do not appear to be linked to Lynch syndrome.

Prostate cancer

A pathogenic variant in a mismatch repair (MMR) gene was discovered in four of 692 men (0.5%) with metastatic prostate cancer and 26 of 1,501 men (1.7%) with prostate cancer but no prior genetic testing. The Prospective Lynch Syndrome Database puts the risk of prostate cancer at 16% for men with an MSH2 pathogenic variant and 5%-7% for men with a pathogenic mutation in one of the other MMR genes.

Sebaceous neoplasms

Sebaceous neoplasms found in Lynch syndrome patients include sebaceous adenomas, epitheliomas, carcinomas, and keratoacanthomas. Sebaceous neoplasms associated with Lynch syndrome have a high MSI. Sebaceous tumors are found in 1%-9% of Lynch syndrome patients.

Endometrial cancer

According to the Prospective Lynch Syndrome Database, persons with MSH2 and MSH6 pathogenic mutations have the highest chance of developing endometrial cancer (46% and 41% by age 70, respectively), followed by MLH1 (35%). Individuals with a PMS2 pathogenic mutation had a risk of endometrial cancer ranging from 12% to 26%, depending on the study.

The average age of endometrial cancer diagnosis ranges from 47 to 50 years for MLH1, MSH2, and PMS2, and from 53 to 55 years for MSH6. Within ten years of receiving their first CRC diagnosis, females with Lynch syndrome have a 26% probability of developing endometrial cancer. Endometrial tumors with MSI have a better prognosis, just like CRC does.

Urinary tract cancers

The most prevalent urinary tract malignancies linked with Lynch syndrome are transitional carcinomas of the ureter, renal pelvis, and kidney. Individuals with Lynch syndrome are also more likely to get bladder cancer. Risk estimates for urinary tract malignancies vary greatly depending on the individual's gender and the gene implicated. Individuals with Lynch syndrome and a past diagnosis of CRC are also at higher risk for subsequent bladder cancer and other urinary tract cancers (kidney, renal pelvis, and ureter).

Brain tumors

According to the National Danish Hereditary Nonpolyposis Colorectal Cancer Register, primary brain tumors were found in 41 of 288 Lynch syndrome families (14%), primarily in those with an MSH2 pathogenic mutation. The most common histological subtype was glioblastoma (56%), followed by astrocytoma (22%), and oligodendroglioma (9%).

Breast Cancer

Data from the Prospective Lynch Syndrome Database indicate an 8%-13% risk by age 70, which is consistent with cohort studies and represents a slight increase over the general population. So far, there is insufficient evidence to justify extra screening beyond population-based breast cancer screening recommendations or those based on personal or family history of breast cancer.

Lynch Syndrome Variants

Muir-Torre syndrome 

Muir-Torre syndrome is a rare form of Lynch syndrome in which individuals appear with a mix of sebaceous neoplasms of the skin and one or more visceral malignancies, similar to those observed in Lynch syndrome. Sebaceous skin neoplasms include adenomas, epitheliomas, carcinomas, and keratoacanthomas.

Turcot syndrome

Turcot syndrome is a historical term that describes people who have CRC, one or more colorectal adenomas, and central nervous system malignancies. Turcot syndrome is typically caused by a pathogenic mutation in one of the MMR genes or an APC pathogenic variant. APC pathogenic mutations are more typically related to medulloblastoma. Pathogenic variants in MMR genes are more commonly associated with glioblastoma.

Constitutional MMR deficiency

Constitutional MMR deficiency (CMMRD) is a rare childhood cancer risk disease characterized by biallelic pathogenic mutations in MLH1, MSH2, MSH6, or PMS2. Before reaching their second decade of life, many affected people develop CRC or small intestine cancer. A family history of Lynch syndrome, consanguineous parents, and/or at least one parent with clinical Lynch syndrome symptoms all raise the possibility of CMMRD. However, if the family history is negative, this diagnosis should not be ruled out, as many children with CMMRD do not have a family history consistent with Lynch syndrome. 

Diagnosis

The National Comprehensive Cancer Network publishes screening guidelines for Lynch syndrome that are currently in use. The National Comprehensive Cancer Network advises immunohistochemical staining of the mismatch repair proteins in all colorectal cancer tumors in patients under 70 years of age, in patients over 70 who meet Bethesda criteria, and in patients under 50 years of age who have endometrial tumors diagnosed.

Microsatellite instability testing and/or immunohistochemistry staining are the two techniques used to screen for Lynch syndrome. These tests have been proven to be very sensitive and specific, with a false negative rate of approximately 5% to 10%.

Immunohistochemistry staining

Immunohistochemical labeling is used on tumor samples to detect the expression of proteins produced by mismatch repair genes. Staining for expression of all mismatch repair proteins indicates that a mismatch repair gene mutation is improbable. This is a normal outcome known as mismatch repair-proficient. If staining shows no expression of at least one mismatch repair protein, this is referred to as mismatch repair-deficient, and germline genetic testing should be offered. It is worth noting that if immunohistochemical staining for MLH1 (alone or with PMS2) is aberrant (not expressed) in colorectal tumor tissue, testing for BRAF V600E mutation or hypomethylation of the MLH1 promoter (in blood or normal tissue) should be performed. If this test is positive, it suggests sporadic colorectal cancer rather than Lynch syndrome; if negative, germline mutation testing for Lynch syndrome should be performed. 

Microsatellite instability testing

Another screening test for Lynch syndrome is microsatellite instability, which is defined as differences in the length of repeated DNA sequences known as microsatellites in the human genome caused by a decrease of mismatch repair activity. The microsatellite instability technique involves testing for nucleotide markers. If a tumor contains a particular proportion of aberrant microsatellite repeat markers, it is classified as having high microsatellite instability. Mismatch repair proficiency is often equivalent to low microsatellite instability. The vast majority of Lynch syndrome tumors have microsatellite instability-high; however, this pattern can also be found in sporadic colorectal cancers, hence germline testing is advised for microsatellite instability-high tumors.

Among sporadic colorectal tumors, 10% to 15% have a deficit in at least one mismatch repair protein and/or have substantial microsatellite instability, which is most typically caused by aberrant methylation of the MLH1 gene promoter rather than Lynch syndrome. As a result, screening for microsatellite instability and/or immunohistochemical staining alone is insufficient to identify Lynch syndrome; germline mutation testing must be performed afterward. This is performed via DNA sequencing and massive rearrangement analysis. Because of the difficulties of test selection, genetic counseling should come before genetic testing. 

Patients who have abnormal immunohistochemical staining and/or abnormal microsatellite instability testing but no germline testing reveal a mutation may have a double somatic mismatch repair gene mutation in the tumor DNA or undetected Lynch syndrome, and their management should be based on their personal/family history.

Clinical testing criteria are based on personal and family history.

Lynch syndrome is diagnosed by taking a detailed family cancer history that includes both maternal and paternal relatives, as well as at least three generations of first, second, and third-degree relatives. All cancers should be documented, including the age at diagnosis if possible. Patients who meet the following criteria should get genetic testing for Lynch syndrome:

  • Endometrial cancer diagnosed before the age of fifty.

  • Known Lynch syndrome in the family.

  • Testing should also be recommended in patients with at least 5% risk of Lynch syndrome.

Amsterdam II Criteria and Revised Bethesda Guidelines.

Amsterdam II Criteria

More than three relatives with Lynch syndrome-related cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis) matching the following criteria:

  • More than two successive generations are affected.

  • One is a first-degree relative of the other two.

  • More than one relative is diagnosed younger than 50.

  • There is no evidence of familial adenomatous polyposis (FAP).

Revised Bethesda Guidelines

  • Colorectal cancer diagnosed in a patient under the age of fifty.

  • The presence of synchronous or metachronous colorectal or other Lynch syndrome-related tumors, regardless of age.

  • Colorectal cancer with microsatellite instability and high histology (tumor-infiltrating lymphocytes, Crohn's lymphocytic response, mucinous or signet-ring differentiation, or medullary growth pattern).

  • Colorectal cancer diagnosed in a patient with one or more first-degree relatives with a Lynch syndrome-related cancer, one of the malignancies detected before the age of 50.

  • Colorectal cancer identified in individuals with two or more first- or second-degree relatives with Lynch syndrome-related malignancies, regardless of age. 

Lynch syndrome-related cancers include colorectal, endometrial, gastric, ovarian, pancreatic, ureter and renal pelvis, biliary tract, brain (often glioblastoma as observed in Turcot syndrome), and small intestinal tumors, as well as sebaceous gland adenomas.

The Amsterdan and Bethesda criteria for identifying patients with Lynch syndrome overlook roughly 50% of cases, while approximately 50% of patients who satisfy the criteria do not have Lynch syndrome.

Individuals identified by tumor testing with immunohistochemical staining and/or microsatellite instability or meeting testing criteria are advised to consider Lynch syndrome-specific gene testing or multi-gene testing of affected family members; however, if no affected member is available, testing of unaffected individuals is recommended.

Management and Treatment

Individuals who have a detrimental Lynch syndrome mutation are more likely to get cancer, with colorectal and endometrial malignancies being the most common, followed by gastric and ovarian cancer. Fortunately, risk management strategies for Lynch syndrome carriers have been linked to fewer cancer-related fatalities. The recommended surveillance for Lynch syndrome carriers is listed below:

Screening/Risk Reduction Guidelines for MLH1, MSH2, MSH6, PMS2, and EPCAM Mutant Carriers

Colon

Colonoscopy should begin at age 20 to 25 and be repeated every one to two years, or two to five years before the onset of colorectal cancer if diagnosed before the age of 25.

Colectomy

Can be performed if colon cancer is diagnosed or if an advanced adenoma is discovered that cannot be removed through other means. Because surgical care is developing, the decision to perform a segmental or extended segmental colectomy for patients with confirmed adenocarcinoma and/or adenomatous polyps is dependent on individual circumstances and risk assessment. Follow-up surveillance with a lower endoscopic check is recommended every one to two years following surgery.

Endometrium (uterus) and ovaries in females

Pelvic exam, transvaginal ultrasound, endometrial aspiration, and/or CA-125 can all be considered individually. The efficacy of this regimen is unknown.

Any abnormal uterine/vaginal bleeding requires quick attention.

Other Extracolonic Cancers (MLH1, MSH2, and EPCAM Mutation Carriers Only)

The risk of other Lynch syndrome-related malignancies is known to be low in MSH6 and PMS2 carriers. 

  • Upper endoscopy (esophagogastroduodenoscopy) with prolonged duodenoscopy every three to five years, beginning at age 30 to 35, may be considered in certain individuals or families, particularly those of Asian heritage. Consider testing and treating H. Pylori.

  • Consider starting urinalysis on an annual basis between the ages of 30 and 35.

  • At this time, no further surveillance for central nervous system/brain and pancreatic cancers is indicated beyond the annual physical/neurologic examination that begins at age 25 to 30.

  • Despite research indicating an increase in pancreatic cancer risk, no effective screening tools have been developed, hence there are no guidelines at this time.

  • It should be noted that it is uncertain if individuals with Lynch Syndrome have an increased risk of developing breast cancer; thus, breast cancer screening is currently focused on personal and family history.

Nonsteroidal anti-inflammatory medications (NSAIDs)

The efficacy of nonsteroidal anti-inflammatory medications in Lynch syndrome patients is being investigated. There is evidence that aspirin use may lower the incidence of colon cancer in Lynch syndrome, although the optimal dose and duration remain unknown.

Preventative interventions

Modifiable risk factors

The majority of data on modifiable risk factors, such as poor diet, excessive alcohol consumption, smoking, lack of exercise, and a high body mass index (BMI), are extrapolated from sporadic CRC cohorts. Weak evidence for LS implies a decreased risk of CRC in those who consume more fruit and a higher risk in smokers. Subgroup analysis from the Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) trial found a strong link between obesity and CRC risk.

Chemoprophylaxis

In LS, only aspirin is advised for chemoprophylaxis. Its potential benefit was originally revealed by meta-analyses that linked long-term use to decreased rates of all malignancies, particularly proximal CRC. Subsequently, the CAPP2 trial, which included 861 LS patients, found that taking 600mg/day of aspirin for 2-4 years was associated with a considerably decreased incidence of all LS-related malignancies after 10 years. A subsequent continuing trial, CAPP3, tries to identify optimal dose, although international guidelines have differed in their use of the CAPP2 findings.

Endoscopic and surgical management

There is a dearth of data on sophisticated endoscopic procedures for removing early-stage colorectal tumors in LS, hence surgical resection is the preferred method. Non-LS colorectal polyps are managed endoscopically according to guidelines. As a result, it is crucial to maximize full resection rates in LS-associated polypectomies, especially for flat serrated polyps.

Surgery plays two roles in LS-associated CRC: it resects the advanced neoplastic lesion and lowers the likelihood of metachronous illness. The risk of metachronous disease applies mostly to MHL1 and MSH2 pathogenic variant carriers, hence, in this context, most guidelines support the use of prolonged colectomy for a first CRC, particularly in younger patients.

Oncological management

Chemotherapy

Systemic anti-cancer treatment choices for LS-CRCs were traditionally limited to the four chemotherapeutic drugs used in sporadic CRCs (fluorouracil, leucovorin, oxaliplatin, and irinotecan), with no regard for MSI or MMR status. Studies on the efficacy of these therapies in MSI-high CRCs were contradictory, not specific to LS, and had small sample sizes. A single LS-CRC-specific retrospective research demonstrated no survival benefit from adjuvant fluorouracil. Nonetheless, these medicines continue to be used as adjuvant treatment for select high-risk or late stage MSI-H/dMMR CRCs, both sporadic and LS-associated.

Immunotherapy

MMR-deficient CRCs had higher levels of immunogenicity than MMR-proficient ones. MMR deficiency allows for the accumulation of point mutations in microsatellite sequences, which can cause translational frameshifts, resulting in carboxy-terminal frameshift peptides (FSPs) that act as "neoantigens" recognized and stimulated by the anti-tumour immune response. The immunoreactive characteristics of MSI-high/dMMR CRCs promoted the adoption of checkpoint inhibitors.

The phase three KEYNOTE-177 trial found that pembrolizumab (anti-PD1) doubled median progression-free survival compared to conventional treatment (16.5 vs 8.2 months). As a result, pembrolizumab has been approved by the US Food and Drug Administration and is recommended as first-line treatment in the UK for metastatic MSI-high/dMMR CRCs. Nivolumab, a second PD-1 inhibitor, has also been authorized by NICE for treatment in conjunction with ipilimumab after conventional combination chemotherapy.

Vaccines

The overwhelming evidence for the interaction between host immune surveillance and LS tumors has provided the conceptual foundation for the use of vaccines to boost the adaptive immune response in LS. The high prevalence of foreign FSPs in LS makes them ideal vaccination targets. Although not explicitly studied in LS-CRC, FSP-based immunization resulted in strong humoral and T-cell responses in a first-in-human, phase I/IIa clinical trial in a mouse model of conditional MSH2 deletion. The same concepts explain the use of cancer vaccines to prevent tumor growth from premalignant polyps by targeting CRC-associated antigens such as MUC1 and CEA, a theory that is now being tested in mice models and has shown encouraging results.

Genetic Counseling

Predictive genetic testing for Lynch syndrome can determine whether or not a person has inherited a mutation that puts them at high risk for cancer. Individuals considering testing for a future health-related risk require knowledge, not simply information, about the genetic contribution to disease in their family. Promoting predictive genetic testing within the context of genetic counseling enables the interpretation of complex genetic information to aid decision-making, improve coping strategies, and promote preventative measures. Individuals who test positive for mutations can be recruited in a targeted screening program to discover colorectal cancer at an early and potentially curable stage, whereas those who test negative can be removed from close surveillance. 

The genetic counselling process guarantees that the psychological significance of the condition, as well as the potential consequences of the genetic test result, are fully discussed, ensuring that the individual is capable of coping with a positive or negative outcome.

When should you see a doctor or genetic counselor about Lynch syndrome?

  • You or someone in your family developed colon cancer before 50 years of age

  • Your family has a history of endometrial cancer

  • You have multiple relatives with tumors of the colon, ovaries, stomach, small intestine, kidney, brain, or liver

  • More than one generation of your family is affected by a particular type of cancer

The extent to which your risk increases is determined by which gene is present in your family and whether you get cancer screening to lower your risk of cancer. However, it is anticipated that 30 to 74 percent of Lynch syndrome patients acquire colorectal cancer; 28 to 60 percent of women suffer endometrial cancer; 5 to 8 percent develop stomach cancer; and 4 to 11 percent develop ovarian cancer. The risk of other Lynch syndrome-related cancers is lower, although significantly higher than the general population rate.

The only established ways to lower cancer risk are regular cancer tests and, if necessary, preventative surgery. Screening aids in the early detection of cancer, when treatment is most effective. Depending on the family, screenings should begin between the ages of 20 and 25, or ten years before the earliest age of cancer diagnosis in the family. If you have Lynch syndrome but have not been diagnosed with cancer, your doctor will develop a personalized cancer screening plan for you.

Conclusion

Lynch syndrome carriers are more likely to develop colorectal cancers as well as extracolonic cancers of the endometrium, gastric, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain (typically glioblastoma as seen in Turcot syndrome), small intestinal cancers, sebaceous gland adenomas, and keratoacanthoma (as seen in Muir-Torre syndrome). Colorectal cancer screening has proven to be effective in detecting and reducing mortality, but the effectiveness of screening for extracolonic malignancies is unknown. Ongoing research may help to better define risk and establish criteria for screening, surveillance, and treatment of Lynch syndrome carriers.