Hereditary Non-Polyposis Colon Cancer

[Lynch Syndrome, HNPCC. Includes: Muir-Torre Syndrome, Turcot Syndrome]

Clinical Diagnosis

The diagnosis of hereditary non-polyposis colon cancer (HNPCC) can be made on the basis of the Amsterdam clinical criteria or on the basis of molecular genetic testing for germline mutations in one of several mismatch repair (MMR) genes.

In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer established the Amsterdam Criteria to define HNPCC for the purpose of identifying families for research studies. These criteria were thought to be too restrictive for clinical purposes and were later modified (Amsterdam II Criteria) to include the other HNPCC-related cancers (Table 1).

Accuracy of Amsterdam Criteria. The accuracy of a diagnosis based upon clinical criteria is dependent on the accuracy of the reported family history, suggesting that diagnostic criteria for HNPCC are not reliable unless the diagnoses of family members are verified [Katballe et al 2001]. Confirming diagnoses with pathology reports and obtaining information regarding family screening behaviors, prophylactic surgeries (e.g., hysterectomy), and polyp history facilitate accurate diagnosis.

The sensitivity and specificity of the Amsterdam Criteria for identifying a mutation in the mismatch repair genes MSH2 and MLH1 have been reported to be 61% and 67%, respectively. The sensitivity is increased to 78% using the Amsterdam II Criteria. However, broadening the criteria decreases the specificity.

Note: Multivariate models indicate that younger age at diagnosis of colorectal cancer, fulfillment of Amsterdam Criteria, and the presence of endometrial cancer in the family are independent predictors of the presence of germline mutations of MSH2 or MLH1 [Wijnen et al 1998b].

Syngal et al [2000] determined that up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam Criteria; however, this study did not incorporate molecular testing methods that detect large deletions or genomic rearrangements, possibly resulting in an underestimation of the sensitivity of the criteria.

Families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history.

More recent studies that compare cancer risk in families meeting Amsterdam Criteria whose tumors exhibited microsatellite instability (MSI) to cancer risk in families meeting the criteria but whose tumors did not exhibit microsatellite instability suggest that the Amsterdam Criteria likely identified families with a variety of genetic etiologies, not just HNPCC [Abdel-Rahman et al 2005, Lindor et al 2005, Mueller-Koch et al 2005]. Therefore, criteria based on family history alone may not be able to distinguish between cases caused by mismatch repair mutations and cases resulting from other as-yet unidentified predisposition genes. Incorporation of MSI status or information from molecular testing is necessary for an accurate diagnosis of HNPCC.

Testing

Microsatellite instability (MSI) testing of tumor tissue. Genes in the mismatch repair (MMR) pathway are responsible for identifying and repairing single nucleotide mismatches and insertion or deletion loops that occur as cells grow and divide [Gruber & Kohlmann 2003]. Defects in the genes involved with mismatch repair lead to an accumulation of somatic mutations in a cell, which may result in the cell becoming malignant. Microsatellites are stretches of DNA with a repetitive sequence of nucleotides (e.g., AAAAA or CGCGCGCG) that are particularly susceptible to acquiring errors when mismatch repair gene function is impaired. Cancers arising in cells with defective mismatch repair gene function exhibit an inconsistent number of microsatellite nucleotide repeats when compared to normal tissue, a finding referred to as "microsatellite instability."

A panel of five markers is used to assess microsatellite instability in tumor tissue and normal tissue. A tumor is classified as follows [Boland et al 1998]:

• MSI-high if more than 30% of the markers show instability

• MSI-low if fewer than 30% of the markers show instability

• MSI-stable if 0% of the markers show instability

Note: (1) Although most clinical laboratories use additional markers when performing MSI testing, there is a lack of consensus on the markers beyond the five designed by Boland et al [1998]. (2) In some tumors microsatellite instability cannot be detected because of technical challenges such as lack of DNA in extremely mucinous tumors [Hampel et al 2005]. (3) The clinical significance of MSI-low tumors remains unresolved.

Approximately 90% of colon cancers from families meeting Amsterdam Criteria are MSI-high [Thibodeau et al 1993, Aaltonen et al 1994, Liu et al 1996, Cunningham et al 2001].

Note: The data available to calculate the sensitivity of MSI testing in identifying individuals with mismatch repair gene mutations are limited because molecular testing is often only pursued in individuals with tumors exhibiting MSI.

Ten to 20% of colon cancers occurring in individuals who are not known to have or suspected of having HNPCC have MSI caused by silencing of the MLH1 gene by methylation or caused by somatic mutations of the mismatch repair genes [Thibodeau et al 1993, Liu et al 1996, Cunningham et al 2001].

The likelihood of detecting a germline mutation in an individual with an MSI-stable tumor is extremely low. Two studies with combined data on approximately 1,000 unselected Finnish individuals with colon cancer did not detect germline mutations in individuals who had MSI-stable tumors [Aaltonen et al 1998, Salovaara et al 2000]. A study by Wahlberg et al [2002] also reported 100% sensitivity for MSI testing in identifying individuals with a germline MLH1 or MSH2 mutation. However, in a few reports, germline mutations were identified in individuals with MSI-stable tumors [Liu et al 1999, Hampel et al 2005].

Although MSI testing of tissue from colorectal carcinoma is clearly preferable, MSI testing can sometimes be performed on tissue from an adenomatous polyp. However, the small amount of tissue obtained during a polyp biopsy may be insufficient for performing MSI testing. When adequate tissue is available, studies of HNPCC-associated adenomas suggests a slightly lower rate of MSI, with approximately 80% of adenomas being MSI-high. Adenomas exhibiting high-grade dysplasia are more likely to exhibit instability, while MSI is much less frequently observed in early polyps [Iino et al 2000]. The occurrence of MSI in sporadic polyps is low [Aaltonen et al 1994, Loukola et al 1999, Pedroni et al 2001]. Therefore, identifying MSI in an adenoma has been found to be a good predictor of an underlying germline mismatch repair mutation [Loukola et al 1999]. However, because many early HNPCC-related adenomas do not exhibit MSI, absence of MSI in these samples does not rule out HNPCC.

Immunohistochemistry (IHC) of tumor tissue. IHC detects the presence or absence of the protein products expressed by mismatch repair genes. IHC is most commonly clinically available for detection of the proteins encoded by MLH1, MSH2, and MSH6. IHC can be performed on tumors demonstrating MSI to help identify the specific mismatch repair gene most likely to have a germline mutation or somatic silencing [de Leeuw et al 2000, Cunningham et al 2001]. However, not all germline mismatch repair gene mutations result in absent protein [Wahlberg et al 2002].

Although absence of protein expression for one or more of the mismatch repair proteins is highly correlated with MSI status [Lindor et al 2002], Hampel et al [2005] found that the combination of IHC and MSI detected all heterozygotes for mutations in mismatch repair genes (23/23), while each method alone missed 2/23 cases. Similar results have been reported by others [Mangold et al 2005]. While a combined approach of IHC and MSI testing of tumors is ideal, IHC may be more feasible for large scale screening programs because it is more available than MSI testing.

Methylation analysis of tumor tissue. The majority of MSI is caused by somatic methylation of MLH1, which can be detected with clinically available testing. Methylation status, along with other molecular features of the newly described serrated pathway of colon tumorgenesis such as the presence of BRAF mutations [Young et al 2005], may be used to identify individuals likely to have a germline MLH1 mutation [Domingo et al 2004, Young et al 2005].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. Four genes are involved in the mismatch repair pathway known to be associated with HNPCC:

• MLH1

• MSH2

• MSH6

• PMS2

Germline mutations in:

• MLH1 and MSH2 account for approximately 90% of families with HNPCC [Peltomaki 2003];

• MSH6 account for approximately 7%-10% of families with HNPCC [Miyaki et al 1997, Berends et al 2002, Peltomaki 2003];

• PMS2 account for fewer than 5% of families with HNPCC.

Other loci

• A mutation in the PMS1 gene was originally reported in a single family; however, this alteration was not found to segregate with the cancers in the family. Further analysis identified a mutation in the MSH2 gene [Liu et al 2001, Peltomaki 2003]. Therefore, the role of PMS1 in HNPCC is currently being questioned.

• Mutations in MSH3, EXO1, and TGFβR2 have been reported in some families with HNPCC; however, the clinical significance of these genes in HNPCC has not yet been determined and clinical testing is not available [Lu et al 1998, Peltomaki 2003].

Clinical uses

• Diagnostic testing

• Confirmatory diagnostic testing

• Predispositional testing

• Prenatal diagnosis

• Preimplantation genetic diagnosis

Clinical testing

• Mutation scanning and sequence analysis. Mutation scanning and sequence analysis of MLH1, MSH2, and MSH6 are available on a clinical basis.
  
  Note: Typically, neither mutation scanning techniques nor sequence analysis can detect large deletions or gene rearrangements.

• Deletion/rearrangement analysis. At least 20% of mutations in MSH2 and 5% of mutations in MLH1 are large deletions or genetic rearrangements [Wijnen et al 1998a, Charbonnier et al 2000, Wagner et al 2003]. Southern blot analysis and multiplex ligation-dependent probe amplification (MLPA) analysis can identify large deletions in MLH1 and MSH2. Although MLPA analysis is a technically easier method of screening for large deletions, some studies have found an increased risk for false-positive and false-negative results with this method because some mutations affect the binding of the probes [Baudhuin et al 2005].

Reseach testing

• Conversion analysis. Casey et al [2005] found that conversion analysis improved the mutation detection rate achieved by sequence analysis alone by 33%. Many of the mutations identified through conversion analysis and missed by sequence analysis were large deletions and rearrangements that would have been detected by Southern blot analysis or MLPA. Conversion analysis also helped clarify the previously undetermined functional significance of several splice site mutations identified by sequence analysis [Casey et al 2005]. See Table 2.

Table 2. Likelihood of Detecting a Germline Mismatch Repair Gene Mutation Based on Selection Criteria

Clinical Criteria 1	Germline Mutation in MSH2 or MLH1
Amsterdam Criteria (classic)	40%-80%
~ Amsterdam II Criteria	0%-50%
Bethesda Guidelines 2 , MSI-H tumor	~50%
Bethesda Guidelines 2	~20%
Unselected CRC, MSI-H tumor	8%-14%
Unselected CRC, loss of MSH2 protein	~100% (MSH2)
Unselected CRC, loss of MLH1 protein	~8% (MLH1)

Nystrom-Lahti et al [1996], Aaltonen et al [1998], Heinimann et al [1999], Salovaara et al [2000], Syngal et al [2000], Cunningham et al [2001], Mitchell et al [2002], Wahlberg et al [2002], Wagner et al [2003], Lipton et al [2004]

CRC = Colorectal cancer

MSI-H = Microsatellite instability-high

1. Reported mutation detection rates can vary depending on:

Family history criteria. Studies using relaxed family history criteria may include more families with histories of cancer caused by chance or other genetic factors not related to mismatch repair mutations. Simple descriptions of clinical criteria do not offer good predictions of mutation detection, as several factors wfithin the family history independently predict the probability of a detectable mutation [Wijnen et al 1998b].

Testing method. Many early studies did not incorporate methods of detecting large deletions or genetic rearrangements, significantly reducing the mutation detection rate.

2. See Bethseda Guidelines.

Table 3 summarizes molecular genetic testing for this disorder.

Table 3. Germline Mutation Detection Rate for HNPCC by Gene and by Test Method

Gene	Mutation Detection Frequency by Gene and Test Method			Test Availability
	Mutation Scanning 1	Full Sequencing	Deletion Analysis (Southern Blot/MLPA)
MLH1	60%-69%	90%-95%	5%-10%	Clinical
MSH2	50%-69%	50%-80%	17%-50%	Clinical
MSH6			Rare	Clinical

Mitchell et al [2002], Solomon et al [2002], Wagner et al [2003], Grabowski et al [2005], Pistorius et al [2006]

1. Methods include: IVSP (in vitro synthesized protein assay), SSCP (single-strand conformational polymorphism assay), DGGE (denaturing gradient gel electrophoresis), DHPLC (denaturing high performance liquid chromatography)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

To view a testing strategy developed by the National Comprehensive Cancer Network, click here (pdf; Adobe^®Acrobat Reader required).

MSI testing of tumor tissue and IHC testing of tumor tissue to target molecular genetic testing for a germline mutation and thus, reduce overall testing costs

Initial Bethesda Guidelines [1997]. The Bethesda Guidelines [Rodriguez-Bigas et al 1997] were developed to identify those individuals whose tumors are candidates for MSI testing. These criteria have been reported to have a sensitivity of approximately 94% and a specificity of approximately 25% [Syngal et al 2000]. Studies have suggested that use of Bethesda Guidelines, modified to include individuals diagnosed with colon cancer before age 50 years, is effective in identifying which individuals with colon cancer actually have HNPCC [Aaltonen et al 1998, Salovaara et al 2000, Cunningham et al 2001].

Updated Bethesda Guidelines [2004]. The Bethesda Guidelines were formally updated in order to increase the sensitivity [Umar et al 2004]:

• Colorectal cancer diagnosed in an individual younger than than age 50 years

• Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors ¹, regardless of age

• Colorectal cancer with the MSI-H histology ² diagnosed in an individual younger than age 60 years

• Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one cancer diagnosed before age 50 years

• Colorectal cancer diagnosed in two or more first- or second-degree relatives of any age.

1. HNPCC cancers included colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma).
2. Presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern

While 2004 Bethesda criteria are more inclusive than the original criteria from 1997, a study by Hampel et al [2005] found that 5/23 probands with mismatch repair mutations did not meet the 2004 criteria.

Molecular testing for germline mutations in individuals who meet the Bethesda Guidelines and have MSI-H tumors and/or have abnormal IHC

Foregoing MSI testing and proceeding directly to germline molecular genetic testing in families meeting the Amsterdam Criteria and in families in which suitable tumor tissue is not available (suggested in some guidelines):

• Testing can be completed in one step if a germline mutation is detected.

• If a germline mutation is not identified, MSI and IHC in tumor tissue may be pursued.

Genetically Related (Allelic) Disorders

Mutations in MLH1, MSH2, MSH6, and PMS2 are not associated with any other phenotypes.

Natural History

Individuals with hereditary non-polyposis colon cancer (HNPCC) caused by a germline mutation in a mismatch repair gene or associated with tumors exhibiting MSI have an increased risk for colon cancer and other cancers including cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin (Table 4).

Colon cancer. Individuals with HNPCC have an approximately 80% lifetime risk for colon cancer. Two-thirds of these cancers occur in the proximal colon [Lynch et al 1993, Lynch & Smyrk 1996, Aarnio et al 1999].

Previous studies conducted with high-risk HNPCC cohorts indicated an average age of diagnosis of 44 years. More recent population-based data have suggested a later age of diagnosis; Hampel et al [2005] reported an average age of diagnosis of 61 years.

Hampel et al [2005] reported lifetime risks for colon cancer to be 69% for men and 52% for women.

When matched stage for stage, colon cancers in individuals with HNPCC are associated with a better prognosis than sporadic colon cancers [Watson et al 1998], an unexpected finding because the poorly differentiated histology of HNPCC-related colon cancers is typically associated with a poor prognosis. Histologic characteristics of HNPCC-related colon cancers include: poor differentiation, tumor-infiltrating lymphocytes, mucin, and signet ring or cribiform histology.

Endometrial cancer. Women with HNPCC have a 20%-60% lifetime risk of endometrial cancer, the second most common cancer in HNPCC [Watson et al 1994, Aarnio et al 1995, Aarnio et al 1999]. The average age of diagnosis of endometrial cancer has been reported to be 46-62 years. A survival advantage similar to that in HNPCC-related colon cancer has been reported in HNPCC-related endometrial cancers [Maxwell et al 2001]. Among women with HNPCC who develop both colon cancer and endometrial cancer, approximately 50% present first with endometrial cancer [Watson et al 1994, Lu et al 2001].

Gastric cancer. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years. Intestinal-type adenocarcinoma, the most commonly reported pathology of HNPCC-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 mutations in CDH1 [Guilford et al 1999].

Ovarian cancer. The mean age of diagnosis of HNPCC-associated ovarian cancers is 42.5 years; however, diagnosis at very young ages has been reported. Approximately 30% of HNPCC-associated ovarian cancers are diagnosed before age 40 years.

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

Other cancers. Other HNPCC-related cancers that have characteristic features have been reported:

• Urinary tract cancers specifically associated with HNPCC are transitional carcinomas of the ureter and renal pelvis.

• The duodenum and jejunum are the most common sites for small bowel cancers. The majority of small bowel cancers are adenocarcinomas [Rodriguez-Bigas et al 1998].

• The most common type of central nervous system tumor is glioblastoma [Hamilton et al 1995].

• Breast cancer, hematologic cancers, and laryngeal cancer have also been reported in families with HNPCC, but consistent associations have not been demonstrated [Gruber 2002, Muller et al 2002, Teruya-Feldstein et al 2002, Westenend et al 2005].

HNPCC variants

• Muir-Torre syndrome. Muir-Torre syndrome is defined by the combination of sebaceous neoplasms of the skin and one or more internal malignancies, commonly those seen in HNPCC. The types of sebaceous skin neoplasias described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Schwartz & Torre 1995, Misago & Narisawa 2000]. Sebaceous neoplasms associated with Muir-Torre syndrome exhibit MSI, as do other HNPCC-related cancers [Entius et al 2000, Machin et al 2002].

• Turcot syndrome. Turcot syndrome is defined as colorectal cancer 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.
  The molecular basis of most cases of Turcot syndrome is either a mutation in the APC gene, which is associated with familial adenomatous polyposis (FAP), or a mutation in the mismatch repair genes associated with HNPCC [Hamilton et al 1995]. Individuals with APC mutations typically have more polyps; however, a significant overlap in polyp number occurs between individuals with Turcot syndrome caused by APC mutations and those with Turcot syndrome caused by mismatch repair gene mutations [Hamilton et al 1995]. The pathology of the CNS tumor can help distinguish between the underlying genetic causes: APC mutations are more commonly associated with medulloblastoma; mismatch repair mutations are more commonly associated with glioblastoma.
  The brain tumors associated with mismatch repair mutations exhibit MSI [Hamilton et al 1995, Suzui et al 1998].

• Homozygous mismatch repair mutations. Rare individuals who are homozygous for mutations in MLH1, MSH2, and PMS2 have been reported. Affected children have onset of colon cancer prior to the second decade of life. Hematologic cancer, brain tumors, and café-au-lait macules have also been reported [Lucci-Cordisco et al 2003].

Genotype-Phenotype Correlations

All HNPCC-related cancers have been reported in individuals who have either MLH1 or MSH2 mutations; however, mutations in MSH2 may be associated with a greater risk for extracolonic cancers than mutations in MLH1. Until more specific genotype/phenotype correlations can be identified, any family meeting the clinical diagnostic criteria for HNPCC or found to have a mutation in either MSH2 or MLH1 should be considered at increased risk for all HNPCC-associated cancers.

MSH2 mutations have been reported more commonly than MLH1 mutations in individuals with the Muir-Torre variant of HNPCC [Kruse et al 1998].

Mutations in MSH6 are associated with MSI-low tumors. The cancers in families with MSH6 mutations may be later onset and distally located; endometrial cancer is commonly associated [Wu et al 1999, Berends et al 2002]. Slightly lower risks for colon cancer and higher risks for endometrial cancer have been reported in families with MSH6 alterations than in individuals with MLH1 or MSH2 mutations [Berends et al 2002].

PMS2 mutations have been reported in families with Turcot syndrome [Hamilton et al 1995].

Genetic modifiers of cancer risk in HNPCC have been reported. Zecevic et al [2006] found that shorter IGF1-CA repeats are associated with an increased risk (HR=2.36; 95% CI=1.28 to 4.36) for colon cancer and earlier age of onset (44 vs. 56.5 years) among individuals who have mismatch repair (MMR) mutations. The p.R462G variant of the gene RNASEL has also been reported to be associated with an earlier age of onset, with an average age of onset of 40 years for individuals with the R/R genotype and 34 years for individuals with the G/G genotype [Kruger et al 2005].

Penetrance

Penetrance of colon cancer associated with mutations in the mismatch repair genes is less than 100% (see Table 4). Therefore, some individuals with a cancer-predisposing mutation in the mismatch repair genes never develop colon cancer.

Anticipation

One study reporting anticipation in HNPCC (i.e., offspring having a younger age of onset than the parents) [Westphalen et al 2005] has not been reproduced. Another study in which offspring had a younger age of onset than their parents determined that this observation was due to birth cohort bias [Tsai et al 1997].

Nomenclature

HNPCC has also been referred to as Lynch syndrome, in recognition of the work of Dr. Henry Lynch in defining the disorder. In the past, Lynch syndrome was divided into Lynch syndrome 1 and Lynch syndrome 2 to differentiate families that only had colon cancer from those that had colon and other HNPCC-associated cancers. However, this distinction is no longer made, and all families with HNPCC should be considered at risk for all HNPCC-associated cancers.

Prevalence

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

Evaluations Following Initial Diagnosis

See Surveillance.

Treatment of Manifestations

Management of colon cancer in a person with hereditary non-polyposis colon cancer (HNPCC). If colon cancer is detected, full colectomy with ileorectal anastomosis is recommended rather than a segmental/partial colonic resection because of the high risk of metachronous cancers [Lynch et al 1988, Aarnio et al 1995, Church & Simmang 2003].

Because the diagnosis of HNPCC is often not considered until after treatment of an initial cancer, many individuals diagnosed with HNPCC have previously had their cancer treated with a limited colonic resection.

Although timing may be difficult, evaluating the tumor biopsy specimen by MSI and IHC (and, if indicated, the MHL1 promoter methylation status) may help determine the optimal surgical approach. A recent study suggests that persons with colon cancer are open to being approached about genetic testing at the time of their diagnosis [Porteous et al 2003].

Prevention of Primary Manifestations

Prophylactic removal of the uterus and ovaries (prior to the development of cancer) can be considered after childbearing is completed.

See Other.

Surveillance

Cancer surveillance

• Colon cancer. Regular colonoscopy with removal of precancerous polyps reduces the incidence of colon cancer in individuals with HNPCC [Jarvinen et al 2000]. Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in HNPCC [Lynch & Smyrk 1996]. Experts recommend that individuals at risk for HNPCC-related colon cancer undergo colonoscopy every one to two years beginning between age 20 and 25 years or ten years before the earliest age of diagnosis in the family, whichever is earlier [Burke et al 1997, National Comprehensive Cancer Network 2006].

• Gynecological cancer. Endometrial cancer and ovarian cancer surveillance is less well established than that for colon cancer.
  
  Because many endometrial cancers can be diagnosed at early stages on the basis of symptoms, women should be educated about the signs of endometrial cancers.
  
  In addition to an annual pap smear and pelvic examination, annual transvaginal ultrasound examination, office endometrial sampling, and CA-125 blood test beginning between age 30 and 35 years (or 5-10 years before the earliest diagnosis in the family) can be considered [Burke et al 1997, Brown et al 2001, National Comprehensive Cancer Network 2006]. For premenopausal women, this screening is recommended between days one and ten of the menstrual cycle.
  
  The efficacy of this screening is unclear. 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]. Further studies are needed to determine if the combination of transvaginal ultrasound examination and endometrial biopsy detect endometrial cancers at an early age.
  
  No specific ovarian cancer screening trials have been conducted in women with HNPCC.

• Stomach and duodenum. Upper endoscopy surveillance is available to screen for gastric and duodenal cancers.
  
  One study suggested no benefit from this screening for gastric cancer because of the lack of identifiable precursor lesions [Renkonen-Sinisalo et al 2002].
  
  In a review of small bowel cancers in a cohort with HNPCC, Schulmann et al [2005] found that approximately 50% of the small bowel cancers were located in the duodenum, suggesting that upper endoscopy may be useful for screening. However, no trials have been conducted to determine the efficacy of upper endoscopy for screening for duodenal cancers.

• Hepatobiliary tract. At this time, no specific screening recommendations for hepatobiliary tract cancers exist.

• Urinary tract. Annual urine cytology is an approach for screening for urinary tract cancers. There are no data indicating that such screening leads to earlier diagnosis or improved outcome, but the testing is inexpensive and associated with minimal risks [National Comprehensive Cancer Network 2006]. The optimal age to begin screening for urinary tract cancers has not been determined, but the risk for developing such types of cancer before age 30 years is low.

• Brain/central nervous system. At this time, no specific screening recommendations for brain tumors exist.

Agents/Circumstances to Avoid

Tobacco use increases the risk of CRC in HNPCC [Watson et al 2004].

Testing of Relatives at Risk

If clinical and family history cannot identify from which parent the proband inherited the mismatch repair (MMR) mutation, molecular genetic testing should be offered to both parents to determine which one has the MMR mutation.

Molecular genetic testing for the identified MMR mutation should be offered to all sibs. The sibs should still be considered at risk even if the parents have not had cancer because most cases of HNPCC are inherited.

Each child of an individual with HNPCC has a 50% chance of inheriting the mutation. In general, genetic testing for HNPCC is not recommended for at-risk individuals under age 18 years. However, individuals with HNPCC have been diagnosed with cancer at very young ages [Huang et al 2001], and it is recommended that screening begin ten years before the earliest age of onset in the family. Thus, in some families screening may need to begin before age 18 years.

Therapies Under Investigation

Studies to investigate the usefulness of chromoendoscopy in improving the detection of flat adenomas in the right colon are currently underway.

Chemoprevention research studies

• COX-2 inhibitors have been found to reduce polyp development in individuals at risk for sporadic colon cancer and in individuals with FAP. The effect of COX-2 inhibitors is being investigated in HNPCC.

• Oral contraceptives reduce the risk of endometrial and ovarian cancer in women who are at general population risk. Studies are underway to determine the effect of oral contraceptive use on endometrial cancer and ovarian cancer risk in women with HNPCC.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Because routine colonoscopy is an effective preventive measure for colon cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with HNPCC.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Hereditary non-polyposis colon cancer (HNPCC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with HNPCC have inherited the mutation from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death, not all individuals with an HNPCC-causing gene mutation have a parent who had cancer.

• If clinical and family history cannot identify from which parent the proband inherited the alteration, molecular genetic testing should be offered to both parents to determine which one has the gene mutation.

• The precise new mutation rate for HNPCC 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 mutation.

• Molecular genetic testing for the identified mutation should be offered to all sibs.

• The sibs should still be considered at risk even if the parents have not had cancer because most cases of HNPCC are inherited.

Offspring of a proband. Each child of an individual with HNPCC has a 50% chance of inheriting the mutation.

Other family members of a proband. 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. Offspring of family members found to have mutations or diagnosed with HNPCC-related cancers can be assumed to be at 50% risk. For branches of the family in which the at-risk person died without developing a cancer, Bayesian analysis can be used to help calculate the risk to the offspring.

Specific risk issues. Several factors can hinder the diagnosis of HNPCC based on family history. Screening and removal of precancerous polyps and prophylactic surgery may prevent colon cancer in some at-risk relatives; some may die young and never develop it.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with HNPCC has the disease-causing mutation or clinical evidence of HNPCC, it is possible that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute)

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for HNPCC is available using the same techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression will be. When testing at-risk individuals for HNPCC, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Genetic counseling is recommended prior to making decisions about genetic testing. Brain et al [2005] suggest that a single educational session may be adequate for genetic counseling for asymptomatic adults who are at risk for treatable conditions. However, preparatory information may be helpful in encouraging individuals to reflect on issues not previously considered. Genetic counseling includes discussion of the clinical and psychosocial implications of genetic testing for the individual and for family members. Studies assessing psychological adjustment following genetic testing have not found that learning that one has an HNPCC mutation is associated with adverse psychological outcomes or clinically significant increases in distress. However, subgroups of individuals with HNPCC, such as those with high levels of pre-test distress, poor quality of life, or low levels of social support, have a greater risk for experiencing psychological morbidity [Vernon et al 1997, Dudok de Wit et al 1998, Gritz et al 1999].

Testing of at-risk individuals during childhood. In general, genetic testing for HNPCC is not recommended for at-risk individuals younger than age 18 years. Guidelines established jointly by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should only be performed in individuals younger than age 18 years when it will affect their medical management. It is recommended that the decision to test be postponed until an individual reaches adulthood and can make an independent decision because management for cancer risk associated with HNPCC is not recommended to begin until age 20 years. Since there are rare reported cases of individuals with HNPCC diagnosed with cancer at very young ages [Huang et al 2001], it is recommended that screening begin ten years before the earliest age of onset in the family. In some families, individuals may need to begin screening before age 18 years. (See also the resolution of the National Society of Genetic counselors on genetic testing of children.)

DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for HNPCC is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as HNPCC that have treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see

Molecular Genetic Pathogenesis

Hereditary non-polyposis colon cancer (HNPCC) is caused by mutations in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single nucleotide mismatches or insertions and deletion loops. At least five different proteins are involved with this process, four of which can cause HNPCC [Peltomaki 2003]. The functions of the mismatch repair genes can be disrupted by missense mutations, truncating mutations, splice site mutations, large deletions, or genomic rearrangements.

MLH1

Normal allelic variants. The MLH1 gene is 57,357 kb in length, with 19 coding exons that encode a protein of 756 amino acids.

Pathologic allelic variants. Over 200 different mutations have been reported in MLH1 [Peltomaki 2003, Peltomaki & Vasen 2004]; see Table C, Locus-Specific Databases.

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

Abnormal gene product. MLH1 acts in a recessive manner at the cellular level where there is an absence of functional Mlh1 protein. This is the result of both copies of the gene carry inactivating mutations, which often occurs by the mechanism of loss of heterozygosity (LOH).

MSH2

Normal allelic variants. The MSH2 gene has 16 exons that encode a protein of 934 amino acids.

Pathologic allelic variants. Over 170 mutations have been identified in MSH2 [Peltomaki 2003, Peltomaki 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].

Normal gene product. DNA mismatch repair protein Msh2, the protein encoded by MSH2, forms a heterodimer with either DNA mismatch repair 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. This is the result of both copies of the gene carrying inactivated mutations, which often occurs by the mechanism of loss of heterozygosity (LOH).

MSH6

Normal allelic variants. The MSH6 gene has ten exons that encode a protein of 1360 amino acids.

Pathologic allelic variants. Over 30 mutations have been identified in MSH6 [Peltomaki 2004].

Normal gene product. The protein encoded by MSH6, DNA mismatch repair protein MSH6, forms a heterodimer with DNA mismatch repair 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. This is the result of both copies of the gene carry inactivating mutations, which often occurs by the mechanism of loss of heterozygosity (LOH).

PMS2

Normal allelic variants. The PMS2 gene has 15 exons that encode a protein of 862 amino acids.

Pathologic allelic variants. Germline mutations in PMS2 are rare [Hendriks et al 2006]. Point mutations and large rearrangements have been reported.

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. This is the result of both copies of the gene carrying inactivating mutations, which often occurs by the mechanism of loss of heterozygosity (LOH). While functioning in a recessive manner on the cellular level, most mutations in the mismatch repair genes are inherited in a dominant manner. Defective mismatch repair arises when the normal allele is lost. However, PMS2 mutations have been reported to be inherited in a recessive manner [Deschênes et al 2007].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

Revision History

• 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