Lynch Syndrome

Clinical characteristics.

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and 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. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome.

Diagnosis/testing.

The diagnosis of Lynch syndrome is established in a proband by identification on molecular genetic testing of a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or of an EPCAM deletion.

Management.

Treatment of manifestations: Adenomas of colon: complete endoscopic polypectomy with follow-up colonoscopy every one to two years. For colon cancer, segmental or extended colonic resection is indicated depending on clinical scenario and factors such as age. For individuals with rectal adenocarcinoma, proctectomy or total proctocolectomy is indicated. Other tumors are managed as in the general population.

Prevention of primary manifestations: Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome.

Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 and 25 years or two to five years before the earliest CRC diagnosis in the family, whichever is earlier. Annual education for females regarding the symptoms of endometrial and ovarian cancers. Consider transvaginal ultrasound examination and endometrial biopsy every one to two years. Consider upper endoscopy examination every three to five years beginning between ages 30 and 35 years particularly for individuals with a family history of gastric cancer and those of Asian ancestry. Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed. Consider capsule endoscopy and small bowel enterography for distal small bowel cancers. Consider urine analysis with urine cytology to identify microscopic hematuria in those with a family history of urothelial cancer. Consider pancreatic cancer screening in individuals with a family history of pancreatic cancer with alternating endoscopic ultrasound and/or MRI/magnetic resonance cholangiopancreatography.

Agents/circumstances to avoid: High body mass, cigarette smoking, type 2 diabetes, and high cholesterol.

Evaluation of relatives at risk: When a diagnosis of Lynch syndrome has been confirmed in a proband, molecular genetic testing for the Lynch syndrome-related pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Genetic counseling.

Lynch syndrome caused by a heterozygous germline pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or by an EPCAM deletion is inherited in an autosomal dominant manner. Individuals with Lynch syndrome caused by constitutional inactivation of MLH1 by methylation typically represent simplex cases but families with non-mendelian inheritance of hypermethylation have been reported. The majority of individuals with Lynch syndrome inherited a pathogenic variant from a parent; however, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

A diagnosis of Lynch syndrome should be suspected in a proband with:

• A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on tumor tissue testing:
  • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click here.)
  • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click here.)
  • Next-generation sequencing in tumor tissue revealing MSI
  • Identification of a pathogenic variant in tumor tissue in an MMR gene
• A diagnosis of colorectal cancer (CRC) or endometrial cancer and one or more of the following:*
  • Colorectal or endometrial cancer diagnosed before age 50 years
  • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic)
  • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern)
  • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years
  • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis
• A family member with colorectal or endometrial cancer who meets one of the above criteria
  Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested.
• A family member with a confirmed diagnosis of Lynch syndrome (pathogenic variant in one of the genes listed in Table 1)
• A ≥5% probability of having a pathogenic variant in one of the genes listed in Table 1 based on risk assessment models
  Note: Several risk assessment models including PREMM5 [Kastrinos et al 2017], MMRPredict [Barnetson et al 2006], and MMRPro [Chen et al 2006] predict the likelihood of identifying a germline pathogenic variant in one of the genes listed in Table 1. Some data suggest utilizing a lower threshold of ≥2.5% for the PREMM5 predictive model.

* Adapted from revised Bethesda Guidelines and National Comprehensive Cancer Network Guidelines; click here (no-fee registration and login required).

Population screening strategies for Lynch syndrome. Lynch syndrome screening guidelines for individuals have been developed by the NCCN; click here (no-fee registration and login required).

Screening approaches include:

• Screen all CRC and endometrial cancers with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [EGAPP 2009, Ladabaum et al 2011, Moreira et al 2012, Mange et al 2015]. (For information on universal tumor testing, including advantages and disadvantages of IHC and MSI testing, see Hampel et al [2018].)
• Use age of onset, familial cancer history, and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [Rabban et al 2014].
• Tumor tissue sequence analysis for a pathogenic variant in one of the genes listed in Table 1 can simplify the screening and provide additional prognostic and/or treatment information [Hampel et al 2018, Salvador et al 2019]. Note: Simultaneous tumor tissue and germline testing that includes analysis of the genes listed in Table 1 may become the preferred approach because it will (1) simplify the screening protocol, (2) reduce the need for reflex testing, and (3) provide additional prognostic or treatment information [Hampel et al 2018, Salvador et al 2019].

Targeted molecular genetic testing on tumor tissue. Approximately 15% of sporadic CRCs have evidence of MMR deficiency. Determining which CRCs are not due to a Lynch-associated germline pathogenic variant is possible with additional tumor tissue testing on either all CRCs with MSI or on tumors with absence of MLH1/PMS2 on IHC. Targeted tumor tissue testing includes the following:

• MLH1 promoter methylation analysis. 10%-15% of CRCs are MSI high or MMR deficient due to somatic methylation of the MLH1 promoter silencing gene expression in the tumor tissue.
  Note: Lynch syndrome-related cancers do not have hypermethylation of the MLH1 promoter (see Differential Diagnosis, Sporadic Colorectal Cancer) unless there is constitutional inactivation of MLH1 by promoter methylation.
• Targeted analysis of BRAF pathogenic variant p.Val600Glu (p.V600E)
  Note: (1) Somatic BRAF pathogenic variant c.1799T>A (p.Val600Glu; NM_004333.4) rarely occurs in colorectal tumor tissue in individuals with Lynch syndrome, while it is present in approximately 15% of all CRCs (see Differential Diagnosis, Sporadic Colorectal Cancer). (2) BRAF pathogenic variants are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome related. (3) Tumor tissue MLH1 promoter methylation testing is currently considered a more effective screening test for Lynch syndrome than somatic targeted sequence analysis for BRAF p.Val600Glu [Newton et al 2014].

Establishing the Diagnosis

The diagnosis of Lynch syndrome can be established in a proband by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1 using molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a multigene panel or DNA methylation studies (see Option 1), and serial single-gene testing (see Option 2). Comprehensive genomic testing (see Option 3) may also be considered.

Clinical Description

Individuals with Lynch syndrome are at increased risk for colorectal cancer (CRC) and other cancers including those of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate (Table 3).

Dowty et al [2013], using sophisticated statistical methodology, revealed that the average risk of cancer (represented in Table 3) does not accurately represent the distribution of cancer risk in individuals with Lynch syndrome. For example, while the average risk of CRC could be 30%-40%, a significant proportion of people with Lynch syndrome have a low risk for CRC (<10%) and a significant proportion have a high risk of developing CRC (>80%). The distribution of cancer risks is due to genetic and/or environmental modifiers.

Colorectal cancer (CRC). The risk of developing CRC associated with MLH1 and MHS2 pathogenic variants is significantly higher than the risk associated with MSH6 or PMS2 pathogenic variants. Of note, risk estimations based on cohort studies compared to the Prospective Lynch Syndrome Database are higher, particularly for PMS2 (9%-20% vs 3%). The mean ages at onset for CRC in individuals with MSH6 and PMS2 pathogenic variants are older than for CRC associated with MLH1 and MSH2 pathogenic variants: 42-69 years for MSH6 and 61-66 years for PMS2, compared with 44 years for MLH1 and MSH2 [Gupta et al 2019, NCCN 2020]. These data explain why CRC screening in individuals with an MLH1 or MSH2 pathogenic variant should start earlier than in individuals with an MSH6 or PMS2 pathogenic variant unless family history suggests otherwise.

CRCs with MSI tend to have a better prognosis in a stage-wise comparison than MSS tumors, potentially reflecting active anti-tumor immune responses. Moreover, treatments supporting the anti-tumoral immune response, such as the immune checkpoint blockade therapy, showed great success in MSI-high tumors [Le et al 2017].

The risk of recurrent CRC is increased in individuals with Lynch syndrome. A meta-analysis of six studies including a total of 871 individuals found that based on an average of 91 months' follow up, the rate of metachronous cancers was 23% among those individuals who had a segmental colectomy, compared to 6% among individuals who had a colectomy (colectomy defined as subtotal or colectomy with ileosigmoid anastomosis) [Anele et al 2017]. The risk of metachronous CRC may be as high as 43% for individuals with an MLH1 or MSH2 pathogenic variant who have segmental resection. Available data indicate that risks of metachronous CRC may be lower for individuals with an MSH6 pathogenic variant, and negligible or absent for those with a PMS2 pathogenic variant.

Endometrial cancer. According to the Prospective Lynch Syndrome Database, the highest risks for endometrial cancer occur in those with MSH2 and MSH6 pathogenic variants (46% and 41% by age 70, respectively), followed by MLH1 (35%), also agreeing with cohort studies [Gupta et al 2019]. In individuals with a PMS2 pathogenic variant, the risk of endometrial cancer is 12%-26%, depending on the study type.

The mean age at endometrial cancer diagnosis is between 47 and 50 years for MLH1, MSH2 and PMS2, and between 53 and 55 years for MSH6. The risk for subsequent endometrial cancer in females with Lynch syndrome presenting first with CRC has been estimated at 26% within ten years of the initial CRC diagnosis [Obermair et al 2010]. As occurs for CRC, endometrial cancers with MSI show better prognosis [Ramchander et al 2020].

Ovarian cancer risk in females with a germline MLH1, MSH2, or MSH6 pathogenic variant has been found to be 11%-17% by age 70. Risk estimates obtained from cohort studies show high variability. Females with a germline PMS2 pathogenic variant have a relatively low increased risk for ovarian cancer. The mean age of diagnosis of Lynch syndrome-associated ovarian cancer has been reported between age 43 and 46 years. Most Lynch syndrome-associated ovarian cancers are of endometrioid histologic subtype [Crosbie et al 2021]. Borderline ovarian tumors do not appear to be associated with Lynch syndrome [Watson et al 2001].

Gastric and small bowel cancers. The risk of gastric and small bowel cancers in individuals with an MLH1 or MSH2 pathogenic variant is 8%-16%. The risk is relatively low for individuals with an MSH6 or PMS2 pathogenic variant. Intestinal-type adenocarcinoma, the most commonly reported pathology of Lynch syndrome-related gastric cancers [Aarnio et al 1997], differs histologically from the diffuse gastric cancer that is most commonly seen in hereditary diffuse gastric cancer, caused by pathogenic variants in CDH1 [Guilford et al 1999]. However, Capelle et al [2010] reported that up to 20% of Lynch syndrome-related gastric cancers may be the diffuse type.

The duodenum and jejunum are the most common sites for cancer of the small bowel, with approximately 50% in reach of upper endoscopy [Schulmann et al 2005]. The majority of small bowel cancers are adenocarcinomas [Rodriguez-Bigas et al 1998, Schulmann et al 2005].

Urinary tract cancers. The urinary tract cancers most commonly associated with Lynch syndrome are transitional carcinomas of the ureter, renal pelvis, and kidney. Bladder cancer risk is also increased in individuals with Lynch syndrome [Dominguez-Valentin et al 2020]. Risk estimates for urinary tract cancers vary significantly based on the individual's sex and the gene involved (see Table 3). Individuals with Lynch syndrome and a prior diagnosis of CRC are also at increased risk for subsequent bladder cancer (7%) and other urinary tract cancers (kidney, renal pelvis, and ureter) (13%) [Win et al 2013].

Prostate cancer. A pathogenic variant in a mismatch repair (MMR) gene was identified in four of 692 men (0.5%) with metastatic prostate cancer [Pritchard et al 2016], and in 26 of 1,501 men (1.7%) with prostate cancer and no prior genetic testing [Pritzlaff et al 2020]. The Prospective Lynch Syndrome Database estimates the risk of prostate cancer for men with an MSH2 pathogenic variant at 16%, and 5%-7% for men with a pathogenic variant in one of the other MMR genes. The mean age at prostate cancer diagnosis was 59-63 years [Gupta et al 2019].

Brain tumors. Data from the National Danish Hereditary Nonpolyposis Colorectal Cancer Register indicated that primary brain tumors were identified in 41 of 288 (14%) Lynch syndrome families, mainly in those with an MSH2 pathogenic variant. Glioblastoma was the most frequent histologic subtype (56%), followed by astrocytoma (22%) and oligodendroglioma (9%) [Therkildsen et al 2015].

Sebaceous neoplasms described in individuals with Lynch syndrome include sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas. Sebaceous neoplasms associated with Lynch syndrome are typically MSI high [Entius et al 2000, Machin et al 2002]. Sebaceous tumors are detected in 1%-9% of individuals with Lynch syndrome, although the available data are limited [Ponti et al 2006, South et al 2008, Ferreira et al 2020].

Pancreatic cancer. Numerous pancreatic cancer cohort studies have identified individuals with a pathogenic variant in an MMR gene [Grant et al 2015, Salo-Mullen et al 2015, Takeuchi et al 2018, Yurgelun et al 2019].

Phenotype Correlations by Gene

Cancer risks vary among the genes associated with Lynch syndrome (see Table 3).

Germline pathogenic variants in MSH6 and PMS2 are estimated to have lower disease penetrance and older ages at CRC diagnosis [Goodenberger et al 2016, Haraldsdottir et al 2017].

MLH1. Heterozygosity for an MLH1 pathogenic variant is associated with the highest risk for CRC, while the risk for extracolonic cancers is smaller than for MSH2 heterozygotes. MLH1 may also be silenced by constitutional epimutation (MLH1 promoter methylation). In this case, available evidence suggests that constitutional MLH1 epimutations cause a severe Lynch syndrome phenotype, including young age of cancer onset and high risk for multiple primary tumors [Pinto et al 2018].

MSH2. Heterozygosity for an MSH2 pathogenic variant is associated with the greatest risk for extracolonic cancers. MSH2 pathogenic variants have been reported more commonly than a pathogenic variant in the other three MMR genes in individuals with the Muir-Torre variant of Lynch syndrome [Everett et al 2014, Lamba et al 2015, Jessup et al 2016].

MSH6. CRC in individuals with an MSH6 pathogenic variant may be later in onset and more distally located than CRC in individuals with a pathogenic variant in MLH1 or MSH2. Slightly lower risks for CRC and risks for endometrial cancer similar to those of MSH2 heterozygotes have been reported in individuals with an MSH6 pathogenic variant. MSH6-associated cancers may be missed on MSI testing because MSH6 is preferentially involved in the repair of mononucleotide repeats and mononucleotide markers are not included in all MSI panels.

PMS2. Heterozygosity for a PMS2 pathogenic variant is associated with the lowest risk (22%) for any Lynch syndrome-related cancer [Dominguez-Valentin et al 2020]. However, while the overall risk for CRC is lower, age of onset may still be early. A review of 234 individuals with a PMS2 pathogenic variant found that 8% were diagnosed before age 30 [Goodenberger et al 2016].

EPCAM. Deletions of EPCAM that result in epigenetic silencing of MSH2 are associated with a significantly increased risk for CRC. Individuals with an EPCAM deletion typically have early-onset CRC and a CRC cumulative risk up to 75%. Compared to individuals with an MSH2 pathogenic variant, individuals with an EPCAM deletion rarely develop extra-gastrointestinal tumors, including endometrial cancer [Kempers et al 2011].

Genotype-Phenotype Correlations

EPCAM. The risk for extracolonic cancers is dependent on the size of the deletion. 3' EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 pathogenic variants [Tutlewska et al 2013].

Penetrance

Penetrance of CRCs and extracolonic cancers associated with pathogenic variants in an MMR gene or EPCAM is less than 100% (see Table 3). Therefore, some individuals with a cancer-predisposing pathogenic variant in an MMR gene or EPCAM may never develop cancer.

Nomenclature

Lynch syndrome may also be referred to as hereditary non-polyposis colorectal cancer (HNPCC). However, HNPCC currently encompasses Lynch syndrome and all other forms of MMR-deficient and MMR-proficient hereditary nonpolyposis colorectal cancer (even those where a genetic cause has not been identified), whereas the diagnosis of Lynch syndrome requires identification of a pathogenic variant in an MMR gene or EPCAM, or a constitutional MLH1 epimutation.

Prevalence

The population prevalence of Lynch syndrome has been estimated at 1:279 (1 in 1,946 for MLH1, 1 in 2,841 for MSH2, 1 in 758 for MSH6, and 1 in 714 for PMS2) [Win et al 2017]. With the exception of a few founder deletions (see Molecular Genetics), alterations in EPCAM are rare.

Lynch syndrome accounts for approximately 3% of CRCs and 3% of endometrial cancers [Moreira et al 2012, Jiang et al 2019, Kahn et al 2019, Dong et al 2020].

Hereditary Cancer Syndromes

Moderate-Risk Colorectal Cancer (CRC) Predisposition

Multigene panels may include testing for genes and/or variants associated with moderate risk of CRC. For many of these variants there are no clear guidelines for the clinical management of heterozygotes. In many cases, the information from testing for variants associated with moderate penetrance does not change the risk management based on family history alone. Variants associated with moderate risk can confer a roughly twofold increased CRC risk – similar to that associated with having a first-degree relative with CRC [Powers et al 2019].

The most prevalent known variants associated with moderate risk for CRC are listed in Table 5 [Yurgelun et al 2017]. Katona et al [2018] defined a counseling framework for these moderate-penetrance variants based on the estimated CRC risk associated with each variant [Ma et al 2014] and the estimated CRC risk for average-risk individuals.

Sporadic Colorectal Cancer

Sporadic MMR-deficient tumors commonly occur in older individuals (predominantly in females). These tumors show lack of MLH1 protein expression due to MLH1 promoter methylation and are strongly associated with the CpG island methylator phenotype (CIMP) and the serrated route of carcinogenesis related to somatic activating hotspot oncogenic variants in BRAF.

• BRAF-related. Somatic BRAF pathogenic variants, the most common being p.Val600Glu (p.V600E) NM_004333.4, occur in 15% of all CRC and, in rare instances, may be identified in tumor tissue from individuals with Lynch syndrome. In a meta-analysis Bläker et al [2020] showed the frequency of BRAF somatic pathogenic variants in Lynch syndrome-associated tumor tissue was 1.6%. The prevalence of BRAF pathogenic variants in MSI-high CRCs also increased with age. Although effective for screening for Lynch syndrome in older age groups, BRAF testing is cost-inefficient for screening in those with MSI-high CRCs diagnosed before age 50 [Bläker et al 2020].
• Somatic MLH1 promoter methylation. Between 10% and 15% of CRCs are MSI high or MMR deficient due to somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue, rather than due to Lynch syndrome. Sporadic endometrial cancers may also be found to be MSI high or show MMR deficiency due to somatic MLH1 promoter methylation. Tumor MLH1 promoter methylation testing is currently considered a more effective screening test for Lynch syndrome than BRAF p.V600E testing [Newton et al 2014].
  Despite its rarity, analysis for constitutional MLH1 epimutation when MLH1 promoter methylation is identified in a tumor is recommended.
  Individuals in whom a Lynch syndrome-associated germline pathogenic variant is not identified and who have somatic MLH1 promoter methylation are likely to have sporadic cancer. Management and additional surveillance for these individuals should be based on their family history of cancer.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Table 6 are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed.

Because screening colonoscopy with polypectomy is an effective preventive measure for colorectal cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with Lynch syndrome.

Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome. Based on combined experience, several consensus statements and expert reviews including the NCCN, the Mallorca guidelines, and the US Multi-Society Task Force on CRC suggest that aspirin can be considered, taking into account an individual's personal health and comorbidities, in the management of individuals with Lynch syndrome [Vasen et al 2013, Giardiello et al 2014, Gupta et al 2019]. The CAPP2 study used a dose of 600 mg/day, which is much higher than the dose of 75 mg/day found to be effective for reducing the risk for sporadic CRC. The investigators found that taking 600 mg of aspirin daily for 25 months substantially reduces the risk of CRC (HR=0.42, 95% CI 0.19-0.86; p=0.02) after 55.7 months [Burn et al 2011]. Recently, the investigators reported ten-year follow-up data of the CAPP2 trial. They demonstrated that those taking aspirin had a significantly reduced risk of CRC (HR=0.65, 95% CI 0.43-0.97; p=0.035) as compared to the placebo group [Burn et al 2020]. The CAPP3 study is currently under way with the goal of identifying the minimum dose of aspirin for reducing CRC risk in individuals.

Surveillance

Agents/Circumstances to Avoid

There is accumulating evidence that a high body mass, cigarette smoking, type 2 diabetes, and high cholesterol increase the risk of CRC in Lynch syndrome. The direction and strength of observed associations are similar to those for the general population [Win & Scott 2016, Dashti et al 2019].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the Lynch syndrome-related pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome.

• Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not de novo) pathogenic variant.
• If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant.

In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with a Lynch syndrome-related pathogenic variant, screening should begin between ages 20 and 25 years, or two to five years earlier than the earliest diagnosis in the family [Gupta et al 2019]. Therefore, a history of early cancers in the family may also warrant testing prior to age 18.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ideally cancer screening exams would be planned around a pregnancy. An affected female would be encouraged to be current on her cancer screening before attempting to become pregnant. If an affected female is diagnosed with cancer during pregnancy, she should be counseled about cancer treatment options and their potential implications for the fetus.

Therapies Under Investigation

Chromoendoscopy vs narrow band imaging (NBI) vs high-definition white-light colonoscopy for Lynch syndrome surveillance. Two studies compared different colonoscopy imaging modalities against chromoendoscopy. In a study of 138 individuals with Lynch syndrome undergoing back-to-back colonoscopies (first with NBI followed by indigo carmine chromoendoscopy), the adenoma detection rate (ADR) for NBI alone was 20.3% while the ADR for both was 30.4%. A 10.1% difference in detection failed to reach the prespecified noninferiority assumption margin of 5% [Cellier et al 2019]. In another study of 256 individuals with Lynch syndrome randomized to indigo carmine chromoendoscopy versus high-definition white-light colonoscopy, no significant difference in ADR was detected by pancolonic chromoendoscpy (34.4%; 95% CI 26.4%-43.4%) as compared to white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; p=0.28) [Rivero-Sánchez et al 2020]. In both studies, chromoendoscopy better identified flat or diminutive adenomas, but also reported significantly longer withdrawal time with chromoendoscopy.

Oral contraceptives and endometrial cancer risk. Epidemiologic studies have found that use of oral contraceptives for more than one year is associated with significant reduction in endometrial cancer risk (HR 0.39, 95% CI 0.23-0.64) [Dashti et al 2015]. To date there are no prospective trials evaluating the impact of oral contraceptives on endometrial cancer risk. One study has demonstrated reduced endometrial proliferation in women with Lynch syndrome after a three-month course of oral contraceptives [Lu et al 2013]. At this time oral contraceptives are not included in recommendations for women with Lynch syndrome, but they are commonly used for managing routine gynecologic issues and for family planning. Data support that oral contraceptives will likely confer benefits to women with Lynch syndrome similar to those in the general population.

Immunotherapy for Lynch syndrome associated cancers. The development of antibodies to immune checkpoint proteins (anti-PD-1 and anti-CTLA4) demonstrate prolonged T-cell response against cancer cells. The emergence of immune checkpoint inhibitors that manipulate and leverage the immune system represent a breakthrough in treatment of Lynch syndrome-associated (and other MSI-high/MMR-deficient) cancers. Recent studies of the treatment of metastatic MSI-high Lynch associated cancer, not limited to colon cancer, with anti-PD-1 monoclonal antibodies have demonstrated 70% or greater disease control rates [Le et al 2015, Le et al 2017, Overman et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

In most individuals, Lynch syndrome is caused by a heterozygous germline pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM, and is inherited in an autosomal dominant manner.

Individuals with Lynch syndrome caused by constitutional inactivation of MLH1 by methylation typically represent simplex cases (i.e., a single occurrence in a family) but families with non-mendelian inheritance of hypermethylation have been reported [Hitchins et al 2011, Hitchins 2015].

Note: Several factors (in addition to the possibility of a constitutional MLH1 epimutation) can hinder the diagnosis of Lynch syndrome based on family history. Screening and removal of precancerous polyps and prophylactic surgery may prevent colon or endometrial cancer in some at-risk relatives; some who died young from other causes may never have developed cancer.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer.
• If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which parent is heterozygous for the pathogenic variant identified in the proband.
• In the rare event that the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent (and parental identity testing has confirmed biological maternity and paternity), possible explanations include the following:
  • A de novo pathogenic variant in the proband (The precise de novo pathogenic variant rate for Lynch syndrome is unknown but estimated to be extremely low [Win et al 2011].)
  • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.)
• A parent who is heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death. Therefore, an apparently negative family history cannot be confirmed without appropriate molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs (see Evaluation of Relatives at Risk).
• If the proband has a known Lynch syndrome-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the genetic status of the parents is unknown, sibs should be considered at risk for cancers associated with Lynch syndrome (regardless of whether parents have had cancer) and offered molecular genetic testing.

Offspring of a proband. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the Lynch syndrome-related pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the pathogenic variant (as is the case in most families), the parent's family members are at risk (family history or molecular genetic testing can help determine whether maternal or paternal relatives are at risk).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [Gupta et al 2019, NCCN 2020]. Therefore, a history of early cancers in the family may also warrant testing prior to age 18.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of Lynch syndrome, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once a germline heterozygous Lynch syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Lynch syndrome is caused by pathogenic variants in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single-nucleotide mismatches or insertions and deletion loops. Pathogenic variants in four of the MMR genes can cause Lynch syndrome [Peltomäki 2003]. The functions of the MMR genes can be disrupted by missense variants, truncating variants, splice site variants, large deletions, or genomic rearrangements. In addition, germline deletions within EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.

Mechanism of disease causation. Loss of function

Notable variants by gene. Table 10 includes founder and common pathogenic variants in different populations.

Author History

Stephen B Gruber, MD, PhD; USC Norris Comprehensive Cancer Center (2004-2021)
Gregory Idos, MD, MS (2021-present)
Wendy Kohlmann, MS; University of Utah Huntsman Cancer Institute (2004-2021)
Laura Valle, PhD (2021-present)

Revision History

• 4 February 2021 (sw) Comprehensive update posted live
• 12 April 2018 (sw) Revision: Tumor testing table added (Table 2)
• 1 February 2018 (sw) Comprehensive update posted live
• 22 May 2014 (me) Comprehensive update posted live
• 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically
• 11 August 2011 (me) Comprehensive update posted live
• 29 November 2006 (me) Comprehensive update posted live
• 5 February 2004 (me) Review posted live
• 18 April 2003 (sg) Original submission

Published Guidelines / Consensus Statements

• American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available online. 2014. Accessed 5-11-23.
• American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available online. 2000. Accessed 5-11-23.
• American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available online. 2001. Accessed 5-11-23.
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 5-11-23.
• American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). Available online. 2003. Accessed 5-11-23.
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 5-11-23.
• Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. [PubMed]
• Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833-40. [PubMed]
• National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal cancer. 2020.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 5-11-23.
• Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484-93. [PubMed]

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