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Lynch Syndrome

Synonyms: HNPCC, Hereditary Non-Polyposis Colon Cancer

, MS and , MD, PhD.

Author Information

Initial Posting: ; Last Revision: April 12, 2018.

Summary

Clinical characteristics.

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen:

  • CRC: 52%-82% (mean age at diagnosis 44-61 years)
  • Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years)
  • Gastric cancer: 6%-13% (mean age at diagnosis 56 years)
  • Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years).

The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.

Diagnosis/testing.

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

Management.

Treatment of manifestations: For colon cancer, full colectomy with ileorectal anastomosis is recommended. 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.

Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between age 20 and 25 years or two to five years before the earliest age of diagnosis in the family, whichever is earlier. The efficacy of surveillance for cancer of the endometrium, ovary, stomach, duodenum, distal small bowel, urinary tract, and central nervous system is unknown.

Agents/circumstances to avoid: Cigarette smoking.

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 is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition 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 diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

Suggestive Findings

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

  • 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, stomach, small intestinal, hepatobiliary, renal pelvic, ureteral)
    • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern)
    • Microsatellite instability (MSI) testing showing that tumor tissue (e.g., colon, endometrial) is MSI-high (For information on MSI testing including advantages and disadvantages, click here.)
    • Tumor tissue (e.g., colon, endometrial) immunohistochemistry (IHC) demonstrates loss of expression of one or more of the mismatch repair (MMR) gene products: MSH2, MLH1, MSH6, and PMS2. (For information on advantages and disadvantages of IHC testing, click here.)
    • 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
  • A greater-than-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 PREMM1,2,6 [Kastrinos et al 2011] and MMRPro [Chen et al 2006] predict the likelihood of identifying a germline pathogenic variant in one of the genes listed in Table 1. Both models have good predictive value in a clinical and population-based setting when using a 5% threshold for testing [Win et al 2013b, Kastrinos et al 2015].

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

Population screening strategies for Lynch syndrome. Lynch syndrome screening guidelines for individuals with CRC have been developed by the NCCN; click here (no-fee registration and log-in required). The Lynch Syndrome Screening Network was established to help develop best-practice approaches for screening individuals with Lynch syndrome-related cancers and to collect long-term data on the outcomes of these programs [Mange et al 2015].

Screening approaches include:

Targeted molecular genetic testing on tumor tissue should be considered in individuals with MLH1/PMS2 loss of expression on IHC. Targeted testing includes the following:

  • Targeted analysis of BRAF pathogenic variant p.Val600Glu
    Note: (1) BRAF p.Val600Glu is not present in Lynch syndrome-associated colorectal tumors (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.
  • MLH1 promoter methylation analysis on tumor tissue
    Note: Lynch syndrome-related cancers do not have hypermethylation of the MLH1 promoter (see Differential Diagnosis, Sporadic colorectal cancer).

Establishing the Diagnosis

The diagnosis of Lynch syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in one of the genes listed in Table 1.

Molecular genetic testing approaches can include a multigene panel, serial single-gene testing, and more comprehensive genomic testing.

Clinical Characteristics

Clinical Description

Individuals with Lynch syndrome are at increased risk for colorectal cancer (CRC) and other cancers including cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin (Table 3).

Table 3.

Cancer Risks by Gene in Individuals with Lynch Syndrome Age ≤70 Years Compared to the General Population

Cancer
Type
General
Population
Risk
MLH1 and MSH2MSH6PMS2
RiskMean Age
of Onset
RiskRisk
Colorectal5.5%M: 27%-74%
F: 22%-53%
27-46 yrsM: 22%
F: 10%
M: 20%
F: 15%
Endometrial2.7%14%-54%48-62 yrs16%-26%15%
Gastric<1%0.2%-13%49-55 yrsM: 6%
F: 22%
6%
Ovarian1.6%4%-20%43-45 yrs
Small bowel<1%4%-12%49 yrs
Hepatobiliary tract<1%0.2%-4%54-57
Urinary tract<1%0.2%-25%52-60 yrs
Brain<1%1%-4%~50 yrs
Sebaceous neoplasms<1%1%-9%Not
reported
UnknownUnknown
Pancreas1.5%0.4%-4%63-65 yrsUnknownUnknown
Prostate16.2%9%-30%59-60 yrsUnknownUnknown
Breast12.4%5%-18%52 yrsUnknownUnknown

Colorectal cancer. The risk of colorectal cancer (CRC) associated with MLH1 and MHS2 pathogenic variants is significantly higher than the risk associated with MSH6 or PMS2 pathogenic variants. The mean ages at onset for CRC in individuals with MSH6 and PMS2 pathogenic variants are also older than for onset for CRC associated with MLH1 and MSH2 pathogenic variants, 54-63 years and 47-66 years respectively. However, up to 8% of CRCs in PMS2 heterozygotes occur before age 30. Therefore, individuals with MLH6 or PMS2 pathogenic variants should follow the same CRC screening recommendations as MLH1 and MSH2 heterozygotes. A 2009 study of a Finnish cohort with high compliance with screening found no increase in mortality for individuals with Lynch syndrome compared to relatives without the Lynch syndrome-related pathogenic variant, indicating that annual colonoscopy is effective for the prevention and detection of CRC [Järvinen et al 2009].

Data on cancer risks for those with an EPCAM deletion is still limited, but Kempers et al [2011] reported on findings from 194 individuals with an EPCAM deletion. From this cohort they estimated a 75% (95% CI 65-86) cumulative incidence of CRC by age 70 years. The risk for CRC did not differ between those who had only a 3' deletion of EPCAM and those individuals with a deletion that encompassed EPCAM and MSH2. However, only those with an EPCAM deletion that includes MSH2 are at an increased risk for extracolonic cancers [Kempers et al 2011, Tutlewska et al 2013].

Tumors that are MSI-H, either due to sporadic causes or an underlying germline MMR pathogenic variant, tend to have a better prognosis than MSS tumors [Kawakami et al 2015].

Endometrial cancer. The risk for women with EPCAM deletions that encompass MSH2 is similar to that for individuals with MSH2 pathogenic variants.

Among females with Lynch syndrome who develop both CRC and endometrial cancer, approximately 50% present first with endometrial cancer [Lu et al 2005]. The risk for subsequent endometrial cancer to 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].

Overall, a survival advantage similar to that in Lynch syndrome-related CRC has been reported in Lynch syndrome-related endometrial cancers [Maxwell et al 2001].

Gastric cancer. 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 risk for gastric cancer is higher in individuals with Lynch syndrome who reside in countries with a high incidence of H pylori infection [Park et al 2000].

Ovarian cancer risk to females with a germline MLH1 or MSH2 pathogenic variant has been found to be 4%-20%. The mean age of diagnosis of Lynch syndrome-associated ovarian cancer has been reported at between age 43 and 45 years, although diagnosis at very young ages has been reported. Approximately 30% of Lynch syndrome-associated ovarian cancers are diagnosed before age 35 years [Watson et al 2008].

The distribution of pathology types is similar to that seen in sporadic ovarian cancers. Borderline ovarian tumors do not appear to be associated with Lynch syndrome [Watson et al 2001].

Small bowel cancer. The duodenum and jejunum are the most common sites for small bowel cancers, 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 and renal pelvis.

Bladder cancer risk is also likely increased in individuals with Lynch syndrome. A study of Dutch individuals with Lynch syndrome demonstrated a relative risk for bladder cancer of 4.4 for males and 2.2 for females; the majority of tumor tissue available for testing was MSI-H and/or had loss of protein expression by IHC [van der Post et al 2010].

Individuals with Lynch syndrome and a prior diagnosis of CRC were also at increased risk for subsequent bladder cancer (7.22, 95% CI=4.08-10.99) and other urinary tract cancers (kidney, renal pelvis, and ureter) (12.54, 95% CI 7.97-17.94) [Win et al 2013a].

Risk estimates for urinary tract cancers vary significantly based on gender and the gene involved.

Brain tumors. The most common type of central nervous system tumor is glioblastoma [Hamilton et al 1995, Wimmer & Etzler 2008]. The brain tumors associated with pathogenic variants in an MMR gene are typically MSI-H [Hamilton et al 1995, Suzui et al 1998].

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-H [Entius et al 2000, Machin et al 2002]. Data on the frequency of sebaceous neoplasms in individuals with Lynch syndrome are limited. Studies have found that between 1% and 9% of individuals with a germline pathogenic variant in an MMR gene have a sebaceous neoplasm [Ponti et al 2006, South et al 2008].

Other Cancers

Other Lynch syndrome-related cancers that have characteristic features have been reported.

Pancreatic cancer. A study by Kastrinos et al [2009] based on reported family history found an 8.6-fold increased risk up to age 70 years for pancreatic cancer [Kastrinos et al 2009]. A prospective study that followed 446 individuals with an MMR pathogenic variant and 1,029 relatives for a median of five years found an increased risk for pancreatic cancer (SIR, 10.68; 95% CI 2.68-47.70), and no increased risk for individuals without a pathogenic variant [Win et al 2012]. However, other studies have not demonstrated an increased risk [Barrow et al 2009]. Lynch syndrome has been found to be a rare cause of familial pancreatic cancer [Gargiulo et al 2009].

Prostate cancer. Several studies have demonstrated an association with prostate cancer, with the increase in risk ranging from two- to fivefold [Raymond et al 2013b, Haraldsdottir et al 2014, Ryan et al 2014]. Raymond et al [2013b] found that the risk for prostate cancer was increased for males with an MMR pathogenic variant prior to age 60 [Raymond et al 2013b], whereas an analysis by Haraldsdottir et al [2014] did not find earlier age of onset or a more aggressive phenotype in the prostate cancers occurring in individuals with an MMR pathogenic variant. Pritchard et al [2016] identified a pathogenic variant in an MMR gene in four (0.5%) of 692 men with metastatic prostate cancer.

Breast cancer. The relationship between breast cancer and Lynch syndrome is unresolved. A systematic review evaluated 21 studies; 13 did not demonstrate an increased risk for breast cancer in individuals with Lynch syndrome and eight showed an increased risk [Win et al 2013a]. To date, breast cancer risk has only been evaluated in one prospective study. Individuals with an MMR pathogenic variant were found to have a standard incidence ratio for breast cancer of 3.95 (95% CI 1.59-8.13), and the median age of breast cancer diagnosis was 56 years. Tumor tissue IHC in 51% of breast cancers in individuals with an MMR pathogenic variant demonstrated loss of expression for the MMR gene with the germline pathogenic variant. Due to the high frequency of breast cancer in the general population, the presence of sporadic breast cancers complicates analysis of the association with Lynch syndrome.

Additional cancer risks. Several other cancer types have been reported to occur in individuals with Lynch syndrome. In some cases, MSI and/or IHC testing of tumor tissue demonstrated concordance between the extracolonic cancer and the molecular diagnosis of the affected individual. While such findings suggest that the underlying presence of a pathogenic variant in an MMR gene contributed to the development of the cancer, data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome.

  • Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [Sijmons et al 2000, den Bakker et al 2003, Nilbert et al 2009]. Nilbert et al [2009] determined that six of eight sarcomas in individuals with Lynch syndrome exhibited defective MMR, suggesting that sarcomas may also be part of the spectrum of Lynch syndrome tumors. Due to the rarity of sarcomas it may be difficult to determine the magnitude of risk associated with Lynch syndrome.
  • Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had an MMR pathogenic variant identified. This association was further evaluated by case review of 135 individuals with pathogenic MMR variants, which identified two (1.4%) individuals who also had ACC [Raymond et al 2013a].

Lynch Syndrome Variants

Muir-Torre syndrome is a historical term used to describe individuals presenting with the combination of sebaceous neoplasms of the skin and one or more internal malignancies, commonly those seen in Lynch syndrome. The types of sebaceous skin neoplasms described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Misago & Narisawa 2000].

Turcot syndrome is a historical term used to describe individuals presenting with CRC or colorectal adenomas in addition to tumors of the central nervous system. The clinical presentation varies from numerous colonic polyps to a single polyp or colorectal cancer. Turcot syndrome is usually caused by either a pathogenic variant in one of the MMR genes associated with Lynch syndrome or an APC pathogenic variant (see Differential Diagnosis and APC-Associated Polyposis Conditions).

Constitutional MMR deficiency (CMMRD). Rare individuals who are homozygous for pathogenic variants in MLH1, MSH2, MSH6, and PMS2 have been reported. Affected individuals often have onset of colon or small bowel cancer prior to the second decade of life. One third of children with biallelic pathogenic variants in an MMR gene have been reported to have more than ten polyps. Hematologic cancer, brain tumors, and café au lait macules have also been reported [Wimmer & Etzler 2008, Durno et al 2010, Bakry et al 2014]. The cutaneous phenotype in affected individuals may be remarkably similar to that seen in neurofibromatosis type I as nearly all will have café au lait macules [Wimmer 2012, Bakry et al 2014]. Features in the family history that increase suspicion of CMMRD:

  • Family history of Lynch syndrome
  • Consanguineous parents
  • At least one parent with clinical findings of Lynch syndrome

However, this diagnosis should not be excluded if the family history is negative, as a significant number of children with a confirmed diagnosis of CMMRD will not have a family history consistent with Lynch syndrome. Bakry et al [2014] reported that a history of Lynch syndrome cancers was rarely noted in the family members of children with CMMRD.

Phenotype Correlations by Gene

Cancer risks vary among the genes associated with Lynch syndrome.

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 [South et al 2008].

MSH6. Heterozygosity for a pathogenic variant in MSH6 is associated with MSI-low tumors. The colorectal cancers in families with an MSH6 pathogenic variant may be later in onset and more distally located than the cancers in families with Lynch syndrome resulting from a pathogenic variant in one of the other MMR genes; endometrial cancer is commonly observed in females with an MSH6 pathogenic variant [Wu et al 1999, Berends et al 2002]. Slightly lower risks for colorectal cancer and higher risks for endometrial cancer have been reported in families with an MSH6 pathogenic variant than in families with an MLH1 or MSH2 pathogenic variant [Berends et al 2002, Baglietto et al 2010].

PMS2. Heterozygosity for a PMS2 pathogenic variant is associated with the lowest risk (25%-32% risk) for any Lynch syndrome-related cancer [Senter et al 2008]. However, while the overall risk of CRC is lower, age of onset may still be early. A review of 234 PMS2 pathogenic variant carriers 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 colorectal cancer. Kempers et al [2011] reported a low risk for endometrial cancer in those with deletions of EPCAM compared to pathogenic variants in an MMR gene.

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 has also been called hereditary non-polyposis colorectal cancer (HNPCC). Clinicians and researchers working in the area of hereditary colorectal cancer have suggested returning to the use of the original name, Lynch syndrome, to include individuals and families with confirmed pathogenic variants in an MMR gene or EPCAM.

Prevalence

Lynch syndrome accounts for approximately 1%-3% of CRCs and 0.8%-1.4% of endometrial cancers [Kowalski et al 1997, Chadwick et al 2001, Cunningham et al 2001].

The population prevalence of Lynch syndrome has been estimated at 1:440 [Chen et al 2006].

Differential Diagnosis

Attenuated familial adenomatous polyposis (AFAP). This milder presentation of FAP, also caused by pathogenic variants in APC, is characterized by fewer polyps and later age of onset than classic FAP. In AFAP, typically fewer than 100 polyps are observed. Polyps of the gastric fundus and duodenum also occur; however, many of the extracolonic manifestations commonly observed in FAP (e.g., epidermal cysts, dental abnormalities, congenital hypertrophy of retinal pigmented epithelium, desmoid tumors) may be absent in AFAP. Polyps and colorectal cancers associated with AFAP do not usually exhibit MSI. AFAP is inherited in an autosomal dominant manner.

Turcot syndrome is a historical term used to describe individuals presenting with colorectal cancer (CRC) or colorectal adenomas in addition to tumors of the central nervous system. Individuals with an APC pathogenic variant typically have more polyps; however, a significant overlap in polyp number occurs between individuals with Turcot syndrome caused by an APC pathogenic variant and those with Turcot syndrome caused by a pathogenic variant in an MMR gene [Hamilton et al 1995]. The pathology of the CNS tumor can help distinguish between the underlying genetic causes: APC pathogenic variants are more commonly associated with medulloblastoma; pathogenic variants in MMR genes are more commonly associated with glioblastoma.

MUTYH-associated polyposis. Biallelic pathogenic variants in MUTYH (MYH) have been described in individuals with multiple adenomatous polyps. Pathogenic variants in MUTYH have been identified in: (1) approximately 30% of individuals with 15-100 polyps; (2) a small portion of individuals with a classic FAP phenotype who have no identifiable APC pathogenic variant; and (3) individuals with a family history of CRC in the absence of multiple polyps. Inheritance is autosomal recessive.

MSH3-related susceptibility to polyposis and CRC (OMIM 600887). Biallelic germline MSH3 pathogenic variants have been rarely reported in families with multiple adenomatous polyps and early-onset CRC. To date only a few individuals with biallelic MSH3 pathogenic variants have been described; thus, risks for additional tumors or cancers have not been well established. Other features reported in those with biallelic pathogenic variants include duodenal polyps, intraductal papilloma of the breast, astrocytoma, thyroid adenoma, and uterine leiomyoma.

NTHL1-related susceptibility to polyposis and CRC (OMIM 616415). Biallelic NTHL1 pathogenic variants have also been identified in families with autosomal recessive polyposis and an increased risk for CRC. The number of polyps reported in these individuals has ranged from one to greater than 50. The age range of developing CRC is 40 to 65 years. To date only a few families with biallelic NTHL1 pathogenic variants have been described, and specific risks for other cancers have not been determined. However, multiple tumors including breast cancer, meningiomas, bladder cancer, endometrial cancer, and basal cell carcinoma have been reported in affected individuals [Weren et al 2018].

POLE-related susceptibility to CRC (OMIM 615083). Individuals with germline heterozygous POLE pathogenic variants are at increased risk for CRC. These individuals may present with few to numerous polyps. Several additional types of cancer including endometrial, ovarian, ureter, gastric, and astrocytoma have been reported in families of individuals with a POLE pathogenic variant. Endometrial cancers related to germline POLE pathogenic variants may be either MSS or MSI-high [Billingsley et al 2015]. To date, most information about POLE is based on a single recurrent pathogenic variant, p.Leu424Val, and it is unknown if other pathogenic variants may be associated with different risks or phenotypes.

POLD1-related susceptibility to CRC (OMIM 174761). Pathogenic variants in POLD1 have been found to be a very rare cause of hereditary CRC. Germline pathogenic variants in POLD1 have been reported in individuals with either a few or multiple polyps. Endometrial cancer and astrocytoma have also been reported in these families [Bellido et al 2016].

Li-Fraumeni syndrome (OMIM 151623). CRC and other GI cancers are increasingly recognized as a component of Li-Fraumeni syndrome, which is caused by pathogenic variants in TP53 [Mork et al 2015, Yurgelun et al 2017]. Consideration of Li-Fraumeni syndrome should be included in the evaluation of individuals with early-onset CRC.

Hamartomatous polyp syndromes. Several autosomal dominant conditions associated with an increased risk for hamartomatous polyps and CRC can usually be distinguished by their extracolonic manifestations as well as hamartomatous rather than adenomatous pathology:

Hereditary diffuse gastric cancer. The gastric cancers, caused by pathogenic variant of CDH1, are typically adenocarcinomas. Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner.

BRCA1/BRCA2 hereditary breast/ovarian syndrome should be considered when evaluating an individual with a family history of cancer that includes ovarian cancer. Hereditary breast and ovarian cancer syndrome caused by germline pathogenic variants in BRCA1 or BRCA2 is inherited in an autosomal dominant manner.

Moderate-risk CRC predisposition genes. Many families exhibit a familial predisposition to CRC that is not explained by Lynch syndrome or the other high-penetrance conditions described. Analysis of families with multiple individuals with MSS CRC have shown an increased risk for CRC, though typically lower than the risks seen in individuals with pathogenic variants in MSH2 and MLH1. Also, these families do not generally exhibit an increased risk for other Lynch syndrome-associated cancers [Abdel-Rahman et al 2005, Lindor et al 2005, Mueller-Koch et al 2005]. These studies have suggested that other genetic factors, outside of the MMR pathway, are likely contributing to risk.

Table 4.

Genes Associated with Moderate Risk for CRC

GenePathogenic VariantCRC Risk
MUTYHPathogenic variant carriers1.5-2-fold
APCc.3920T>A2-fold
CHEK2c.1100del2-fold 1
1.

Additional increased risk for breast cancer

Sporadic colorectal cancer

  • BRAF-related. BRAF pathogenic variants, the most common being c.1799T>A (p.Val600Glu or V600E) NM_004333.4, occur in 15% of CRCs. BRAF pathogenic variants are thought to be rare in Lynch syndrome-related cancers and, thus, in general the presence of a BRAF pathogenic variant rules out the diagnosis of Lynch syndrome [Bellizzi & Frankel 2009, Bouzourene et al 2010].
  • Somatic MLH1 promoter methylation. The majority of MSI is caused by somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue; thus, the finding of MLH1 promoter methylation can often help eliminate the diagnosis of Lynch syndrome in individuals without additional suggestive features.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Surveillance are recommended, as well as consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Management of colon cancer in a person with Lynch syndrome. If colon cancer is detected, full colectomy with ileorectal anastomosis is recommended rather than a segmental/partial colonic resection because of the high risk for metachronous cancers. 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].

Population-based approaches for screening newly diagnosed individuals with CRC for Lynch syndrome generally rely on analysis of tumor tissue from the surgical resection specimen, but this will not provide information about the diagnosis of Lynch syndrome in time to make decisions about segmental/partial colectomy versus colectomy. For individuals presenting with CRC before age 50 and/or who have a strong family history, proceeding directly to genetic testing could be considered in order to have information about possible hereditary diagnoses in time for surgical planning.

The other tumors seen in Lynch syndrome are managed as in the general population.

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 (see Therapies Under Investigation).

Surveillance

Colorectal cancer (CRC). Colonoscopy with removal of precancerous polyps should be performed every one to two years beginning between age 20 and 25 years or two to five years before the earliest diagnosis in the family, whichever is earlier, for all individuals with Lynch syndrome. Regular colonoscopy with removal of precancerous polyps reduces the incidence of CRC in individuals with Lynch syndrome.

Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome.

Endometrial cancer. Endometrial cancer surveillance is less well established than that for colon cancer.

Educate females about the symptoms of endometrial cancers (e.g., abnormal uterine bleeding, postmenopausal bleeding), because many endometrial cancers can be diagnosed at early stages on the basis of symptoms.

Endometrial biopsy every one to two years can be considered, but to date data do not support that such additional testing improves early detection or outcomes [NCCN 2016].

Studies on the effectiveness of transvaginal ultrasound examination and endometrial biopsy have had conflicting results:

  • In a study of the use of transvaginal ultrasound examination to screen for endometrial cancer, no cancers were detected; however, two cancers were detected on the basis of symptoms manifest during the course of the study [Dove-Edwin et al 2002].
  • A report from a Finnish cohort found that endometrial sampling and transvaginal ultrasound every two to three years resulted in the diagnosis of early-stage cancers. However, because endometrial cancer often presents with symptoms at an early stage, it was not clear that the screening improved detection [Järvinen et al 2009].

Ovarian cancer. No specific ovarian cancer screening trials have been conducted in females with Lynch syndrome.

Educate women about the symptoms that may be associated with ovarian cancer (e.g., pelvic or abdominal pain, bloating, increased abdominal girth, difficulty eating, early satiety, urinary frequency or urgency).

Screening for ovarian cancer using serum CA-125 and transvaginal ultrasound examination has not been effective in other high-risk populations such as females with a BRCA1 or BRCA2 pathogenic variant [Evans et al 2009], but may be recommended at the clinician's discretion.

Gastric and duodenal cancers. Over time, screening recommendations for gastric and duodenal cancers have varied. Studies have not supported that screening improves early detection or outcomes of these cancers, but because the stomach and duodenum are the most common extracolonic non-gynecologic cancer in Lynch syndrome, periodic upper endoscopy exams have been included in guidelines. Upper endoscopy can be considered, particularly for individuals with a family history of gastric cancer and those of Asian ancestry, every three to five years beginning between age 30 and 35 years [NCCN 2016]. Note: Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed [NCCN 2016].

Data regarding the effectiveness of upper endoscopy examination for the early detection of gastric cancer in Lynch syndrome are limited.

  • One study suggested no benefit from this screening for gastric cancer because of the lack of identifiable precursor lesions [Renkonen-Sinisalo et al 2002].
  • A study looking at gastric cancer risk in a Dutch study suggested that the level of risk is sufficient to warrant screening; however, since 87% of the cancers occurred after age 45 years, it may be most cost effective to initiate screening at age 45 years [Capelle et al 2010].
  • Schulmann et al [2005] found that approximately 50% of the small bowel cancers in a cohort with Lynch syndrome were located in the duodenum, suggesting that upper endoscopy may be useful for screening. However, no trials to determine the efficacy of upper endoscopy for screening for duodenal cancers have been conducted.

Distal small bowel. Data are limited regarding screening for cancer in the distal small bowel. Capsule endoscopy and small bowel enterography are available for evaluating the small bowel, but at this time, there is no recommendation for routine use of these approaches for small bowel screening, although they may be helpful for evaluating symptomatic individuals.

Urinary tract. NCCN recommends consideration of annual urine analysis beginning between age 30 and 35 years [NCCN 2016].

Central nervous system. Consider an annual physical exam that includes a neurologic evaluation beginning at age 25 to 30 years. At this time, there is no recommendation for routine imaging to screen for brain tumors.

Other cancers. At this time, no specific screening recommendations for other Lynch syndrome-associated cancers exist. Individuals should be encouraged to follow other general population screening guidelines and to seek prompt medical attention for changes in health or persistent symptoms. As noted previously, individuals with Lynch syndrome may be at increased risk for other cancers such as breast and prostate. However, it is not clear that these risks warrant screening above and beyond what is currently recommended for general population screening for these cancers. If there is a family history of early onset of other cancer types, cancer screening recommendations should be adjusted to begin screening at an earlier age.

Agents/Circumstances to Avoid

Cigarette smoking increases the risk for CRC in Lynch syndrome [Pande et al 2010].

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 age 20 and 25 years, or two to five years earlier than the earliest diagnosis in the family [NCCN 2016]. 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 and Intensive Colonoscopy

A 2008 study compared the effectiveness of chromoendoscopy and intensive colonoscopy inspection in early detection of polyps in persons with Lynch syndrome. Following standard colonoscopy, study participants were randomized to receive a second colonoscopy with chromoendoscopy or a second colonoscopy with careful inspection. This study found that although polyps are frequently missed during standard colonoscopy, no difference was observed between the number of additional polyps detected by chromoendoscopy and by the careful second-look colonoscopy [Stoffel et al 2008].

A more recent study randomized 61 people with Lynch syndrome to standard white light colonoscopy or colonoscopy performed with virtual chromoendoscopy. The virtual chromoendoscopy (also called I-SCAN) is a filter feature that helps highlight subtle changes in the lining, providing a similar effect to traditional chromoendoscopy. Participants then had a repeat scope using the other method. The authors found that virtual chromoendoscopy after standard colonoscopy detected 15 missed polyps, while standard colonoscopy after virtual chromoendoscopy found only two missed polyps [Bisschops et al 2017]. There will likely continue to be improvements in colonoscopy imaging, which will improve detection of polyps and screening outcomes for individuals with Lynch syndrome [Hüneburg et al 2009, Rahmi et al 2015].

Chemoprevention

Use of aspirin can be considered to reduce CRC risk. The Colorectal/Adenoma/Carcinoma Prevention Programme 2 (CAPP2) was a four-arm, randomized trial comparing placebo versus 600 mg/day aspirin and placebo versus resistant starch (Novelose) 30 g/day among 1,071 individuals with Lynch syndrome. At a mean follow up of 29 months, neither aspirin nor starch had an effect on CRC risk [Burn et al 2008]. However, subsequent analysis of the data with a mean follow up of 55.7 months found a 63% reduction in CRC risk (HR 0.41, 95% CI 0.19-0.86; p=0.02) [Burn et al 2011].

While data specifically on the use of aspirin in individuals with Lynch syndrome is limited to the data from the CAPP2 study, several other studies have demonstrated the same effect of aspirin on sporadic CRC [Rothwell et al 2011]. Based on the combined experience several consensus statements and expert reviews including 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, NCCN 2016]. The CAPP2 study used a dose of 600 mg/day, which is much higher than the dose of 75 mg/day that was found to be effective for reducing the risk for sporadic CRC. The CAPP3 study is currently under way with the goal of identifying the minimum dose of aspirin for reducing CRC risk in individuals.

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 to 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.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lynch syndrome is inherited in an autosomal dominant manner.

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.
  • A parent 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.
  • 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 one has the pathogenic variant identified in the proband.
  • In the rare event that the pathogenic variant found in the proband is not detected in leukocyte DNA of either parent, possible explanations include 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 [Bisgaard & Bernstein 2003].

Sibs of a proband

  • Sibs of a proband are at a 50% risk of inheriting the pathogenic variant.
  • Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs.
  • Even if the parents have not had cancer, sibs should still be considered at risk and offered molecular genetic testing because most Lynch syndrome-related pathogenic variants are inherited, not de novo.

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 their relationship to the proband. 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.

Specific risk issues. Several factors 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with Lynch syndrome has the pathogenic variant or clinical evidence of Lynch syndrome, it is possible that the proband has a de novo pathogenic variant. However, a de novo pathogenic variant is thought to be rare, and non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption, could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 younger than 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 beginnning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [NCCN 2016]. 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA)
  • Hereditary Colon Cancer Takes Guts
  • Lynch Syndrome International
    P.O. Box 5456
    Vacaville CA 95688
    Phone: 707-689-5089
    Email: info@lynchcancers.com
  • My46 Trait Profile
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • C3: Colorectal Cancer Coalition
    1414 Prince Street
    Suite 204
    Alexandria VA 22314
    Phone: 877-427-2111 (toll-free); 703-548-1225
    Fax: 202-315-3871
    Email: info@fightcolorectalcancer.org
  • Colon Cancer Alliance (CCA)
    1200 G Street Northwest
    Suite 800
    Washington DC 20005
    Phone: 877-422-2030 (Toll-free Helpline); 202-434-8980
    Fax: 866-304-9075 (toll-free)
  • Prospective Registry of MultiPlex Testing (PROMPT)
    PROMPT is an online research registry for patients and families who have undergone multiplex genetic testing and were found to have a genetic variation which may be linked to an increased risk of having cancer.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Lynch Syndrome (View All in OMIM)

114500COLORECTAL CANCER; CRC
120435LYNCH SYNDROME I
120436MutL, E. COLI, HOMOLOG OF, 1; MLH1
158320MUIR-TORRE SYNDROME; MRTES
185535EPITHELIAL CELLULAR ADHESION MOLECULE; EPCAM
276300MISMATCH REPAIR CANCER SYNDROME; MMRCS
600259POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 2; PMS2
600678MutS, E. COLI, HOMOLOG OF, 6; MSH6
609309MutS, E. COLI, HOMOLOG OF, 2; MSH2
609310COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2; HNPCC2
613244COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 8; HNPCC8

Molecular Genetic 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.

EPCAM

Gene structure. EPCAM comprises nine exons encoding a protein of 314 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Deletions involving the transcription termination signal of EPCAM are causative in 1% to 2.8% of families with Lynch syndrome. Other EPCAM pathogenic variants that do not affect the transcription termination signal cause autosomal recessive congenital tufting enteropathy [Sivagnanam et al 2010] (see Genetically Related Disorders).

Normal gene product. EPCAM expression varies in tissues. High levels of expression were found in colorectal stem cells, while low levels of expression were detected in leukocytes [Ligtenberg et al 2009]. Little is known about EPCAM expression in most other tissues predisposed to Lynch syndrome-related cancers.

Abnormal gene product. EPCAM deletions are thought to arise from Alu-mediated recombination events [Kuiper et al 2011]. Elimination of the EPCAM transcription termination signal results in transcription continuing into MSH2 and silencing of the MSH2 promoter by methylation. Through this mechanism the MSH2 allele in cis configuration with the EPCAM deletion becomes inactivated in the tissues in which EPCAM is expressed, while the other MSH2 allele is unaffected. These deletions are transmitted in an autosomal dominant manner, as are germline variants in genes involved in MMR [Ligtenberg et al 2009].

MLH1

Gene structure. MLH1 is 57,357 kb in length, with 19 coding exons encoding a protein of 756 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 200 different pathogenic variants have been reported in MLH1 [Peltomäki 2003, Peltomäki & Vasen 2004]; see Table A. Deletions account for 5%-10% of germline MLH1 pathogenic variants.

Constitutional inactivation of MLH1 by methylation, along with somatic loss of heterozygosity of the functional allele, has been reported as a rare cause of Lynch syndrome (~0.6%) [Niessen et al 2009]. These individuals have silencing of one MLH1 allele, throughout their tissues, due to methylation of the promoter and a Lynch syndrome phenotype. Most of such cases are simplex (i.e., a single occurrence in a family), but a few families with inherited hypermethylation have been reported [Goel et al 2011]. MLH1 promoter methylation is not detectable by either sequence analysis or duplication/deletion analysis of MLH1.

Normal gene product. DNA MMR protein Mlh1 dimerizes with the product of PMS2 (PMS1 protein homolog 2) to coordinate the binding of other proteins involved with MMR including the helicases, the protein encoded by EXO1, proliferating cell nuclear antigen (PCNA), single-stranded-DNA binding-protein (RPA), and DNA polymerases [Peltomäki 2003].

Abnormal gene product. MLH1 acts in a recessive manner at the cellular level where there is an absence of functional Mlh1 protein in the tumor cells. This results from inactivation of both MLH1 alleles in the tumor, which often occurs as a result of an inactivating variant or silencing of the MLH1 promoter by hypermethylation.

MSH2

Gene structure. MSH2 comprises 16 exons encoding a protein of 934 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 170 pathogenic variants have been identified in MSH2 [Peltomäki 2003, Peltomäki & Vasen 2004]. The higher proportion of Alu repeats may contribute to the higher rate of genomic rearrangements in MSH2 than in MLH1 [van der Klift et al 2005]. At least 20% of germline MSH2 pathogenic variants are exon or multiexon deletions.

Normal gene product. DNA MMR protein MSH2, the protein encoded by MSH2, forms a heterodimer with either DNA MMR protein MSH6 or MSH3 and functions to identify mismatches. A sliding clamp model has been suggested to describe the structure of the heterodimer. Mismatches in the DNA are thought to be detected as the clamp slides along the DNA [Fishel et al 1993, Gruber & Kohlmann 2003].

Abnormal gene product. MSH2 acts in a recessive manner at the cellular level where there is an absence of functional Msh2 protein in the tumor cells. This results from inactivation of both MSH2 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity. MSH2 promoter methylation has been shown to be the inactivating event that silences the normal allele in individuals with an MSH2-inactivating pathogenic variant. Of note, this is not a common cause of sporadic colon cancer.

MSH6

Gene structure. MSH6 comprises ten exons encoding a protein of 1,360 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 30 pathogenic variants have been identified in MSH6 [Peltomäki & Vasen 2004]. Exon or multiexon deletions are a rare cause of germline MSH6 pathogenic variants.

Normal gene product. The protein encoded by MSH6, DNA MMR protein MSH6, forms a heterodimer with DNA MMR protein MSH2 and functions to identify mismatches by a sliding clamp model [Fishel et al 1993, Gruber & Kohlmann 2003].

Abnormal gene product. MSH6 acts in a recessive manner at the cellular level where there is an absence of functional MSH6 protein in the tumor cells. This results from inactivation of both MSH6 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity.

PMS2

Gene structure. PMS2 comprises 15 exons encoding a protein of 862 amino acids. Multiple pseudogenes have been identified at 7p22, 7p12-13, 7q11, and 7q22 [Nicolaides et al 1995]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Germline pathogenic variants in PMS2 are rare [Hendriks et al 2006]. Single-nucleotide variants and large gene rearrangements have been reported. Studies that have included large deletion testing have found that up to 20% of pathogenic variants may be large deletions. Large deletion testing of PMS2 is technically difficult due to the numerous pseudogenes, and it presents significant challenges to laboratories trying to provide comprehensive large deletion testing for the whole gene. The currently available MLPA (multiplex ligation-dependent probe amplification) kit can detect deletions but does not clarify whether the deletion may be in one of the pseudogenes. Testing in coordination with a panel of reference samples can help determine whether deletions are clinically significant [Vaughn et al 2011].

Normal gene product. See MLH1, Normal gene product.

Abnormal gene product. PMS2 acts in a recessive manner at the cellular level where there is an absence of functional PMS2 protein in the tumor cells. This results from inactivation of both PMS2 alleles in the tumor, which often occurs by the mechanism of loss of heterozygosity.

References

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 4-9-18. [PubMed: 24310308]
  • American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available online. 2000. Accessed 4-9-18.
  • American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available online. 2001. Accessed 4-9-18.
  • American Society of Clinical Oncology. Expert statement: collection and use of a cancer family history for oncology providers. Available online. 2014. Accessed 4-9-18. [PMC free article: PMC3940540] [PubMed: 24493721]
  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 4-9-18.
  • 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 4-9-18.
  • 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 4-9-18. [PubMed: 23428972]
  • Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. 2001. [PubMed: 11438509]
  • National Comprehensive Cancer Network. Guidelines for colorectal cancer screening. 2016.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 4-9-18.
  • National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing. 2011. [PubMed: 22167527]

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  • Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, Buchanan DD, Clendenning M, Giles GG, Winship I, Macrae FA, Goldblatt J, Southey MC, Arnold J, Thibodeau SN, Gunawardena SR, Bapat B, Baron JA, Casey G, Gallinger S, Le Marchand L, Newcomb PA, Haile RW, Hopper JL, Jenkins MA. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958–64. [PMC free article: PMC3341109] [PubMed: 22331944]
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Suggested Reading

  • Hampel H, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, LaJeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, de la Chapelle A, Frankel W, Penzone P, Cohn DE, Copeland L, Eaton L, Fowler J, Lombardi J, Dunn P, Bell J, Reid G, Lewandowski G, Vaccarello L. Comment on: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2007;67:9603. [PubMed: 17909073]
  • Rumilla K, Schowalter KV, Lindo NM, Thomas BC, Mensink KA, Gallinger S, Holter S, Newcomb PA, Potter JD, Jenkins MA, Hopper JL, Long TI, Weisenberger DJ, Haile RW, Casey G, Laird PW, Le Marchand L, Thibodeau SN. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011;13:93–9. [PMC free article: PMC3069927] [PubMed: 21227399]

Chapter Notes

Revision History

  • 12 April 2018 (sw) Revision: Tumor testing table (2) added
  • 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 to live Web site
  • 5 February 2004 (me) Review posted to live Web site
  • 18 April 2003 (sg) Original submission
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