Testing

Tests performed on tumor tissue are used:

• To establish the probability of Lynch syndrome; and

• To identify which gene is most likely to have a causative germline mutation in a person with Lynch syndrome.

Plausible etiologies to explain the results of tumor testing and recommended additional testing based on the results of tumor testing are summarized in Table 3.

Tissue type

• Although testing of tissue from colorectal carcinoma is clearly preferable, tests 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 testing.

• Testing can also be used be to screen endometrial cancers for defective MMR [Backes et al 2009].

Distinguishing sporadically occurring tumors from those caused by a germline mutation

• Colon tumors. Testing colon tumor tissue for abnormal methylation of MLH1 and for somatic BRAF mutations may identify tumors that are more likely to be sporadic than the result of a germline mutation in an MMR gene. If the findings from these and other tests of tumor tissue (Table 3) are consistent with Lynch syndrome, germline molecular genetic testing can be pursued.

• Endometrial cancers. BRAF mutations are not common in sporadic endometrial cancers; thus, BRAF testing is not a helpful step for distinguishing sporadic endometrial cancers from those that are Lynch syndrome related [Kawaguchi et al 2009].

Immunohistochemistry (IHC) of tumor tissue. IHC detects the presence or absence of the protein products expressed by mismatch repair genes. The MMR gene products work in dimers: MSH2 protein may complex with MSH6 or MSH3 protein, and MLH1 protein complexes with PMS2 or PMS1 protein. MSH6 and PMS2 proteins are unstable when not paired in a complex; thus, a germline mutation in MSH2 typically results in loss of expression of the proteins MSH2/MSH6 and a germline mutation in MLH1 results in loss of expression of the proteins MLH1/PMS2. However, germline mutations in MSH6 and PMS2 typically do not result in loss of MSH2 or MLH1 expression because these proteins are still present in other pairings [Bellizzi & Frankel 2009].

Advantages of IHC testing

• IHC testing is effective for detecting tumors resulting from MMR deficiency. Antibodies for MSH2, MLH1, MSH6, and PMS2 have demonstrated 92% sensitivity for identifying tumors that arise in individuals with a germline mutation [Shia 2008].

• IHC testing is readily available at most centers and is technically easy to perform.

• IHC testing identifies in most individuals the MMR gene in which either a germline mutation or a somatic alteration that silences gene expression is most likely to be found [de Leeuw et al 2000, Cunningham et al 2001], thus significantly reducing the cost of molecular genetic testing.

Limitations of IHC testing

• Variation in tissue fixation and other technical issues can result in weak or equivocal staining patterns [Shia 2008].

• It is possible that some missense germline mutations will not result in the absence of a detectable protein product [Wahlberg et al 2002, Bellizzi & Frankel 2009].

• It may be less reliable when performed on small tissue samples [Zhang 2008].

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." See Figure 1.

Figure

Figure 1. Microsatellite instability testing is used to identify tumors caused by defective mismatch repair by comparing the number of nucleotide repeats in a panel of microsatellite markers in normal tissue with the number from tumor tissue from the (more...)

MSI, assessed using panel of microsatellite markers, is compared in tumor tissue and normal tissue. A 1997 NCI consensus meeting recommended a core panel of five markers: BAT25, BAT26, D2S123, D5S346, and D17S250 [Boland et al 1998]; however, laboratories often use panels of up to ten markers. A tumor is classified as follows [Boland et al 1998]:

• MSI-high if more than two (or >30%) of the markers show instability

• MSI-low if one (or <30%) of the markers show instability

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

Note: 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].

• Colon tumors. When adequate tissue is available, studies of Lynch syndrome-associated adenomas suggest a slightly lower rate of MSI compared to invasive cancers, with approximately 80% of adenomas being MSI-high (see Table 3). Adenomas with high-grade dysplasia are more likely to exhibit MSI than early polyps [Iino et al 2000].

• Endometrial cancers. Approximately 20%-30% of endometrial cancers exhibit MSI, and as with colon cancers the majority are the result of somatic MLH1 promoter methylation [Hampel et al 2006].

Advantages of MSI testing

• MSI testing is an effective method for determining which tumors arise from MMR deficiency. Studies have demonstrated that the sensitivity of MSI testing for identifying tumors that arise in individuals with a germline MMR gene mutation is 93% [Shia 2008].

• MSI testing may be positive (i.e., identify a tumor as arising from MMR deficiency) when the IHC studies have given a false negative result (e.g., because the appropriate antibody was not included in the test; the protein is present, but non-functional) [Shia 2008].

• MSI testing can be done with very little tissue [Zhang 2008].

• MSI testing is highly reproducible [Zhang 2008].

Limitations of MSI testing

• It may not be readily available at all centers because it requires microdissection and molecular analysis [Bellizzi & Frankel 2009].

• In some tumors MSI cannot be detected because of technical challenges such as lack of DNA in extremely mucinous tumors [Hampel et al 2005].

• It may fail to identify a tumor as arising from MMR deficiency when an MSH6 germline mutation is causative as these tumors tend to have low levels of MSI [Shia 2008].

• It does not reduce the cost of molecular testing because it does not help identify the gene which is most likely mutated.

BRAF testing

• Colon tumors. BRAF mutations, the most common being Val600Glu (V600E), occur in 15% of colorectal cancers. BRAF mutations are thought to be rare in Lynch syndrome-related cancers and, thus, in general the presence of a BRAF mutation rules out the diagnosis of Lynch syndrome [Bellizzi & Frankel 2009, Bouzourene et al 2010].

• Endometrial cancers. BRAF mutations 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 [Kawaguchi et al 2009].

Methylation analysis of tumor tissue. 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.

However, inactivation of the remaining functional allele by methylation can also be the “second hit” that causes homozygous inactivation of the gene, resulting in tumor development in an individual with a germline MLH1 mutation [Bellizzi & Frankel 2009, Niessen et al 2009]. Therefore, the diagnosis of Lynch syndrome cannot be eliminated by the presence of MLH1 promoter hypermethylation in an individual with early-onset colon cancer, strong family history, or other risk factors.

Somatic methylation of the functional MSH2 allele has been found to be the second hit for in approximately 24% of MSH2-related cancers. However, methylation of MSH2 has not been found to be a cause of sporadic colorectal cancers [Nagasaka et al 2010].

Molecular Genetic Testing

Genes. The five genes (MLH1, MSH2, MSH6, PMS2, and EPCAM (formerly known as TACSTD1) in which germline mutations disrupt the mismatch repair (MMR) pathway and cause Lynch syndrome are listed in Table 3.

Note: Although EPCAM is not a MMR gene, recurrent germline deletions of the 3' region of result in silencing of the adjacent downstream MSH2 by hypermethylation [Niessen et al 2009, Goel et al 2011, Kuiper et al 2011].

Evidence for additional locus heterogeneity. There are a few case reports of germline MLH3, MSH3, EXO1, PMS1, or TGFBR2 mutations in some families with Lynch syndrome; however, the clinical significance, if any, of mutations in these genes in Lynch syndrome has not yet been determined [Lu et al 1998, Peltomaki 2003]. A succinct discussion of the evidence of a possible role of these genes in Lynch syndrome can be found at www.omim.org:

• MLH3: 604395. See also .

• MSH3: 600887

• EXO1: 606063

• PMS1: 600258. See also .

• TGFBR2: 190182

The clinical utility of testing for germline mutations in these genes in individuals suspected of having Lynch syndrome is unknown.

Table 3. Summary of Germline Molecular Genetic Testing Used in Lynch Syndrome

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Gene Symbol	Proportion of Lynch Syndrome Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
MLH1	50% 1, 2	Sequence analysis	Sequence variants 3	Clinical
		Duplication/ deletion analysis 4	Exonic or whole-gene deletion 5
MSH2	40% 1	Sequence analysis	Sequence variants 3	Clinical
		Duplication/ deletion analysis 4	Exonic or whole-gene deletion 5
MSH6	7%-10% 6	Sequence analysis	Sequence variants 3	Clinical
		Duplication/ deletion analysis 4	Exonic or whole gene deletion 5
PMS2	<5% 7	Sequence analysis	Sequence variants 3	Clinical
		Duplication/ deletion analysis 4	Exonic or whole-gene deletion 5
EPCAM (TACSTD1)	~1%-3% 9	Duplication/ deletion analysis 4	Exonic or whole-gene deletion 8	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. 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.

1. Peltomaki [2003]

2. Constitutional inactivation of MLH1 by methylation, along with somatic loss-of-heterozygosity of the functional allele, has been reported to be a rare cause of Lynch syndrome. Such cases are not detectable be either sequence analysis or duplication/deletion analysis of MLH1 (see Molecular Genetics).

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. Large deletions and genetic rearrangements account for 20% of mutations in MSH2, 5% of mutations in MLH1, 20% of mutations in PMS2, and 7% of mutations in MSH6, and 100% of mutations in EPCAM [Wijnen et al 1998, Charbonnier et al 2000, Wagner et al 2003, Plaschke et al 2004, Senter et al 2008].

6. Miyaki et al [1997], Berends et al [2002], Peltomaki [2003]

7. Senter et al [2008]

8. Germline deletions of EPCAM result in silencing of the adjacent MSH2 allele by hypermethylation. The adjacent MSH2 allele itself is not mutated (see Molecular Genetics).

9. Niessen et al [2009], Goel et al [2011], Kuiper et al [2011]

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

Testing Strategy

Confirming/establishing the diagnosis of Lynch syndrome in a proband. To view the Colorectal Cancer Screening testing strategy guidelines developed by the National Comprehensive Cancer Network (NCCN), click (no-cost registration and login required). Testing is ideally performed in a stepwise manner:

I. Testing of tumor tissue (Table 2). The availability of MSI and IHC testing allows for the screening of tumor tissue to help identify individuals who may have Lynch syndrome. These methods may be implemented with various strategies:

• Approach 1. Screen all colorectal cancers with MSI and/or IHC testing [EGAPP Working Group 2009]. A 2005 population-based study of 1566 colorectal cancers reported that 25% of individuals found to have a germline mutation in an MMR gene did not meet the Amsterdam Criteria or Bethesda Guidelines.
  
  Note: While a combined approach of IHC and MSI testing of tumor tissue is ideal, use of IHC testing alone may be more feasible for large-scale screening programs because it is more readily available than MSI testing and provides information about which MMR gene most likely harbors a germline mutation. For example, for tumors exhibiting loss of both MLH1 and PMS2 expression, reflex testing of tumor tissue for MLH1 promoter methylation and BRAF mutations can help distinguish sporadic tumors from those more likely to harbor a germline MLH1 mutation.

• Approach 2. Target IHC and/or MSI testing of tumor tissue from individuals with colorectal cancer or other Lynch syndrome-related cancers and additional features that suggest the diagnosis, such as early age of onset or strong family history.
  
  Note: The Bethesda Guidelines were established to help identify individuals who may have Lynch syndrome and who are candidates for MSI and/or IHC testing of tumor tissue [Umar et al 2004]. Although their estimated sensitivity in identifying individuals with Lynch syndrome is up to 94%, their specificity is only 25% [Syngal et al 2000].

II. Molecular genetic testing (Table 3)

• Approach 1. As recommended by the results of tumor testing (Table 2)

• Approach 2. As per one of the following risk assessment models that help predict the likelihood of identifying a germline mutation in one of the Lynch syndrome associated genes

  • PREMM_{1,2, 6} Model is based on data from 4539 individuals undergoing genetic testing of MSH2, MLH1, and MSH6 through a commercial laboratory. This model incorporates information on the Lynch syndrome-related cancers (colon, endometrial, stomach, ovarian, small intestine, urinary tract/kidney, bile ducts, glioblastoma, sebaceous gland tumors, and pancreas) in the proband and in first and second-degree relatives, and age of onset. Data from MSI and IHC testing are not included. Based on genotype/phenotype data, this model provides specific likelihood estimates for detecting a mutation in each of the MMR genes. Using a 5% mutation probability as a standard for MMR testing, the model has an estimated sensitivity of 90% and a specificity of 54% [Kastrinos et al 2011]. The model is also able to use family history to estimate the likelihood that a person who has not had cancer has a mutation in an MRR gene.

  • MMRpredict is based on data from a population-based cohort diagnosed with colorectal cancer before age 55 years who were tested for mutations in MLH1, MSH2, and MSH6. Data from MSI and IHC testing and the presence of colorectal and/or endometrial cancer in first-degree relatives can be incorporated. This model can only be used in affected individuals; it is unclear how accurate the model is for tumors diagnosed in older individuals [Barnetson et al 2006].

  • MMRpro (see also CancerGene) incorporates information on colorectal and endometrial cancers in the proband and first- and second-degree relatives, age of onset, and results of IHC and MSI testing to estimate the likelihood of identifying a germline mutation in MLH1, MSH2, or MSH6 in a family; uses Mendelian modeling to determine the probably that a family member has inherited a germline mutation; and calculates the individual’s risk to develop colon and endometrial cancer.
    
    Mutation data have been obtained from clinic- and population-based data reported in the literature; cancer risk estimates are based on penetrance data from a meta-analysis of five large Lynch syndrome studies. Since this model does not incorporate information on most extracolonic cancers, it is unclear how accurately it can identify the gene most likely to be mutated [Chen et al 2006].

• Approach 3. Foregoing MSI testing and proceeding directly to germline molecular genetic testing in families meeting the Amsterdam Criteria. This approach is not recommended, but may be considered in the two instances outlined below:

  • When no tumor tissue is available for tumor testing:

    • Begin molecular testing with a family member diagnosed with a Lynch syndrome-related cancer.

    • Pursue molecular testing of all four MMR genes and EPCAM. Testing can be done in a stepwise manner beginning with the genes in which a mutation is most likely to be identified.

    • If no germline mutation is identified in any one of the five genes tested, Lynch syndrome still cannot be ruled out because some mutations may be missed, or it is possible that the family member selected for testing had a sporadic (non-genetic) cancer. In this latter instance, molecular genetic testing of another relative with a Lynch syndrome-related cancer may result in detection of a causative germline mutation.

    • In the absence of information on the MSI status of the tumor, it is not possible to distinguish between Lynch syndrome and other causes of familial colorectal cancer.

  • When no tumor tissue or living affected relative is available for testing:

    • Molecular genetic testing to identify a germline mutation could be pursued in an unaffected family member.

    • The likelihood of an unaffected person having a mutation (if one is present in the family) depends on that individual's degree of relatedness to an affected family member (e.g., a first-degree relative has a 50% chance of having inherited a mutation).

    • A cost-benefit analysis suggests that testing unaffected individuals is worth pursuing in such instances because of the significant benefit for the family if a Lynch syndrome causative germline mutation is identified [Dinh et al 2011].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

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

Natural History

Individuals with Lynch syndrome 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. Initial studies based on high-risk kindreds meeting Amsterdam criteria have found up to an 82% lifetime risk for colon cancer, and a mean age of onset of 44 years. Two thirds of these cancers occur in the proximal colon [Lynch et al 1993, Lynch & Smyrk 1996, Aarnio et al 1999].

More recent studies of heterozygotes for an MLH1 and MSH2 mutation have resulted in lower risk estimates of 66%-69% for men and 43%-52% for women, and an average age of diagnosis of 61 years [Hampel et al 2005, Stoffel et al 2009].

Colon cancer risk estimates have also been lower for heterozygotes for an MSH6 and PMS2 mutation. Risks to male and female heterozygotes for an MSH6 mutation up to age 80 years have been found to be 44% and 20%, respectively. While substantially lower than the risk associated with MLH1 and MHS2 mutations, this still represents an eightfold increase in colon cancer risk [Baglietto et al 2010]. The risk to heterozygotes for a PMS2 mutation up to age 70 years was 15%-20% [Senter et al 2008].

Data on cancer risks for those with an EPCAM mutation 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 colorectal cancer by age 70 years. The risk for colorectal cancer did not differ between those who had only a 3’ deletion of EPCAM and those harboring a deletion that encompassed EPCAM and MSH2.

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

Endometrial cancer. Women with Lynch syndrome have a 25%-60% lifetime risk of endometrial cancer, making this the second most common cancer in Lynch syndrome [Aarnio et al 1999, Vasen et al 2001, Hampel et al 2005, Stoffel et al 2008]. Studies based on high-risk families have found an average age of diagnosis of approximately 48 years; population-based studies have revealed a later age of diagnosis (62 years) [Vasen et al 1994, Hampel et al 2005].

While mutation of MSH6 is associated with a more moderately increased colon cancer risk, heterozygotes have a 44% risk for endometrial cancer, similar to the level of risk reported for MLH1 and MSH2 heterozygotes [Baglietto et al 2010]. Among women with Lynch syndrome who develop both colon cancer and endometrial cancer, approximately 50% present first with endometrial cancer [Watson et al 1994, Lu et al 2005]. The risk for subsequent endometrial cancer for women with Lynch syndrome presenting first with colon cancer has been estimated at 26% within ten years of the initial colon cancer diagnosis [Obermair et al 2010].

Kemper et al found a 12% (95% CI 0-27) cumulative risk for endometrial cancer by age 70 years. The risk for women with deletions affecting both EPCAM and MSH2 was similar to that reported for women with an MSH2 mutation [Kempers et al 2011].

Overall, Lynch syndrome accounts for approximately 2% of all endometrial cancers [Hampel et al 2006]. A survival advantage similar to that in Lynch syndrome-related colon cancer has been reported in Lynch syndrome-related endometrial cancers [Maxwell et al 2001].

Gastric cancer. Estimates for gastric cancer risk in heterozygotes for an MLH1 or an MSH2 mutation range from 6% to 13%. The risk is greatest in males with an MSH2 mutation [Watson et al 2008, Capelle et al 2010]. Higher risks have been reported in countries with other risk factors for gastric cancer such as high incidence of H pylori infection [Park et al 2000]. The mean age of diagnosis of gastric cancer is 56 years. 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 mutations in CDH1 [Guilford et al 1999]. However, Capelle et al reported that up to 20% of Lynch syndrome-related gastric cancers may be the diffuse type [Capelle et al 2010].

Ovarian cancer. The risk for ovarian cancer varies by the MMR gene in which the germline mutation occurs. The risk to heterozygotes for an MLH1 mutation has been found to be 4%-6%, while MSH2 heterozygotes have an 8%-11% risk. The mean age of diagnosis of Lynch syndrome-associated ovarian cancers is 42.5 years; however, 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 seem to be associated with Lynch syndrome [Watson et al 2001].

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

• Urinary tract cancers. The urinary tract cancers most commonly associated with Lynch syndrome are transitional carcinomas of the ureter and renal pelvis.
  
  A recent study suggests that bladder cancer risk is likely also increased in Lynch syndrome. A study of a Dutch Lynch syndrome cohort demonstrated a relative risk for bladder cancer of 4.4 for males and 2.2 for females; the majority of tumor tissue available for MSI and/or IHC testing exhibited MSI and/or had loss of protein expression corresponding to the germline mutation [van der Post et al 2010].
  
  Risk estimates for urinary tract cancers vary significantly based on gender and the mutated gene with higher risks seen in males heterozygous for an MSH2 mutation. Women with an MLH1 mutation have an approximately 1% risk while men with an MSH2 mutation have been estimated to have up to a 27% risk [Watson et al 2008].

• Small bowel cancer. The risk for small bowel cancer has been estimated at between 3% and 6% [Watson et al 2008]. 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].

• Pancreatic cancer. A study by Stoffel 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]. 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].

• Brain tumors. The risk for brain tumors is estimated at approximately 2% [Schulmann et al 2005]. However, Barrow et al [2009] estimated a 16-fold increased risk for persons with biallelic MSH2 mutations. The most common type of central nervous system tumor is glioblastoma [Hamilton et al 1995, Wimmer & Etzler 2008].

• Breast cancer. The relationship between breast cancer and Lynch syndrome is unresolved. Studies have not consistently demonstrated a higher than expected incidence. A recent study by Walsh et al [2010] determined that tissue from 51% of breast cancers in individuals with a mutation in an MMR gene exhibited loss of immunohistochemical staining for the protein corresponding to the gene in which a germline mutation occurs.

• Sebaceous skin neoplasias described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Schwartz & Torre 1995, Misago & Narisawa 2000]. Sebaceous neoplasms associated with Lynch syndrome exhibit MSI [Entius et al 2000, Machin et al 2002]. The 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 mutation in an MMR gene have a sebaceous neoplasm [Ponti et al 2006, South et al 2008].

• Additional cancer risks. Although hematologic cancers and laryngeal cancer have also been reported in families with Lynch syndrome, consistent associations have not been demonstrated [Gruber 2002, Muller et al 2002, Teruya-Feldstein et al 2002, Westenend et al 2005, 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.

Lynch syndrome variants

• Muir-Torre syndrome is defined by 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 neoplasias described include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas [Schwartz & Torre 1995, Misago & Narisawa 2000].

• 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.
  
  Turcot syndrome is usually caused either by a mutation of APC (see APC-Associated Polyposis Conditions) or by a mutation in one of the mismatch repair genes associated with Lynch syndrome [Hamilton et al 1995]. Individuals with an APC mutation typically have more polyps; however, a significant overlap in polyp number occurs between individuals with Turcot syndrome caused by an APC mutation and those with Turcot syndrome caused by a mutation in a mismatch repair gene [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; mutations of a mismatch repair gene are more commonly associated with glioblastoma.
  
  The brain tumors associated with mutations in a mismatch repair gene exhibit MSI [Hamilton et al 1995, Suzui et al 1998].

• Homozygous mismatch repair mutations. Rare individuals who are homozygous for mutations 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 mutations 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].

Genotype-Phenotype Correlations

Cancer risks vary among the four MMR genes.

Heterozygosity for an MSH2 mutation is associated with the greatest risk for extracolonic cancers; risk for extracolonic cancers (other than endometrial cancer) is low for heterozygotes with an MSH6, PMS2, or EPCAM mutation.

MSH2 mutations have been reported more commonly than a mutation in the other three MMR genes in individuals with the Muir-Torre variant of Lynch syndrome [South et al 2008].

Heterozygosity for a mutation in MSH6 is associated with MSI-low tumors. The cancers in families with an MSH6 mutation may be later in onset and more distally located than the cancers in families with Lynch syndrome resulting from a mutation in one of the other MMR genes; endometrial cancer is commonly observed in women with an MSH6 mutation [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 an MSH6 mutation than in families with an MLH1 or MSH2 mutation [Berends et al 2002, Baglietto et al 2010].

Heterozygosity for a PMS2 mutation is associated with the lowest risk (25%-32% risk) for any Lynch syndrome-related cancer [Senter et al 2008].

Deletions of EPCAM that result in epigenetic silencing of MSH2 are associated with a significantly increased risk for colon cancer. Studies have shown high levels of EPCAM expression in colonic stem cells; however, because EPCAM is not expressed at high levels in all tissues, the effect of EPCAM on extracolonic cancer risks is unclear. Kempers et al [2011] reported a low risk for endometrial cancer in those with deletions of EPCAM compared to mutation of an MMR gene. Of the 194 individuals with an EPCAM mutation included in this study, 16 developed cancers other than colonic or endometrial, with duodenal (n=3) and pancreatic (n=4) being the most common. Further research is needed to better define the extracolonic cancer risks associated with EPCAM deletions [Kempers et al 2011].

Penetrance

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

Anticipation

One study reporting anticipation in Lynch syndrome (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 caused by birth cohort bias [Tsai et al 1997].

Nomenclature

Lynch syndrome has also been called hereditary non-polyposis colorectal cancer (HNPCC). Clinicians and researchers working in the area of hereditary colon cancer have suggested returning to the use of the original name, Lynch syndrome, to specify individuals and families with defective MMR and to distinguish them from other forms of familial colon cancer [Bellizzi & Frankel 2009, Weissman et al 2011].

Prevalence

Lynch syndrome 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].

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

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Lynch syndrome, the evaluations summarized in Surveillance are recommended.

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 [Lynch et al 1988, Aarnio et al 1995, Church & Simmang 2003]. Note: Because the diagnosis of Lynch syndrome is often not considered until after treatment of an initial cancer, many individuals diagnosed with Lynch syndrome 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 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].

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

Prevention of Primary Manifestations

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

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 Lynch syndrome.

Surveillance

Colon cancer. Regular colonoscopy with removal of precancerous polyps reduces the incidence of colon cancer in individuals with Lynch syndrome. A 2009 study of a Finish cohort with high compliance with screening found no increase in mortality for individuals with Lynch syndrome over their mutation-negative relatives, indicating that annual colonoscopy could help with the prevention and detection of colon cancer [Järvinen et al 2009]. In this study four individuals were diagnosed with colon cancer and lymph node metastases: one was diagnosed during baseline colonoscopy, the other three were diagnosed more than two years after their last colonoscopy. Therefore, current recommendations are to have colonoscopy every one to two years beginning between ages 20 and 25 years or ten years before the earliest diagnosis in the family, whichever is earlier [Järvinen et al 2009, Engel et al 2010, NCCN 2011].

In MSH6 and PMS2 heterozygotes the risk for colon cancer is lower; thus colonoscopy screening may be delayed until age 30 years [Senter et al 2008, Baglietto et al 2010].

Note: Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome [Lynch & Smyrk 1996].

Endometrial cancer. Endometrial 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.

Currently the National Comprehensive Cancer Network (NCCN) does not recommend any specific screening for endometrial or ovarian cancer [NCCN 2011].

Studies on the effectiveness of transvaginal ultrasound examination and endometrial biopsy have had conflicting results. Further studies are needed to determine if the combination of transvaginal ultrasound examination and endometrial biopsy detect endometrial cancers at an early age.

• 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 could not be certain that the screening improved detection [Järvinen et al 2009].

Ovarian cancer. No specific ovarian cancer screening trials have been conducted in women with Lynch syndrome. Of note, screening for ovarian cancer using CA-125 blood tests and transvaginal ultrasound examination has not been effective in other high-risk populations such as women with a BRCA1 or BRCA2 mutation [Evans et al 2009].

Gastric and duodenal cancers. Upper endoscopy surveillance can be used to screen for cancers of the stomach and duodenum. Currently the NCCN recommends beginning upper endoscopy with a side-viewing scope and extended duodenoscopy between ages 30 and 35 years and repeating them every two to three years depending on the findings. Those with evidence of chronic inflammation, atrophic gastropathy, and/or intestinal metaplasia would be candidates for more frequent evaluation. Note: Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed [NCCN 2011].

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. At this time data are limited regarding screening for cancer development in the distal small bowel. Capsule endoscopy every two to three years beginning between ages 30 and 35 years can be considered.

Urinary tract. NCCN recommends consideration of annual urine analysis [NCCN 2011]. The optimal age to begin screening for urinary tract cancers has not been determined; however, the risk of developing such types of cancer is low before age 30 years.

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

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

Agents/Circumstances to Avoid

Cigarette smoking increases the risk of colorectal cancer in Lynch syndrome [Watson et al 2004, Pande et al 2010].

Testing of Relatives at Risk

Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic, at-risk relatives for early manifestations is appropriate.

When an MMR gene mutation has been identified in a family with Lynch syndrome, molecular genetic testing for the mutation should be offered to all first-degree relatives (parents, sibs, and children).

• The 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, mutation.

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

In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, because cancer has been diagnosed in individuals with Lynch syndrome 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 such instances, it is appropriate to offer molecular genetic testing to children younger than age 18 years prior to initiating cancer screening.

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

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]. Further studies are needed to determine if novel colonoscopy techniques confer additional benefit for the screening of persons with Lynch syndrome.

Chemoprevention research studies

• A four-arm trial comparing placebo versus aspirin and placebo versus resistant starch was conducted among 1071 individuals with Lynch syndrome. No effect on the risk for colorectal neoplasia was seen in either the aspirin or resistant starch intervention group [Burn et al 2008].

• Whereas oral contraceptives reduce the risk of endometrial and ovarian cancer in women who are at general population risk, it is unknown if they confer the same benefit in women with Lynch syndrome.

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

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 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 a Lynch syndrome-causing MMR gene mutation have a parent who had cancer.

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

• The precise new mutation 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 mutation.

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

• The sibs should still be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited, not a de novo, mutation .

Offspring of a proband. Each child of an individual with Lynch syndrome 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 Lynch syndrome-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.

Related Genetic Counseling Issues

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.

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

Considerations in families with an apparent de novo mutation. When neither parent of a proband with Lynch syndrome has the disease-causing mutation or clinical evidence of Lynch syndrome, it is possible that the proband has a de novo mutation. However, de novo mutation in an MMR gene is thought to be rare and other possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored [Bisgaard & Bernstein 2003].

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

Testing of at-risk asymptomatic adults for Lynch syndrome is available using the 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 Lynch syndrome, 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 a Lynch syndrome mutation is associated with adverse psychological outcomes or clinically significant increases in distress. However, subgroups of individuals with Lynch syndrome, such as those with high levels of pre-test distress, poor quality of life, or low levels of social support, are at greater risk of experiencing psychological morbidity [Vernon et al 1997, Dudok de Wit et al 1998, Gritz et al 1999].

Molecular genetic testing of asymptomatic 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. 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 Lynch syndrome is not recommended to begin until age 20 years. Since there are rare reported cases of individuals with Lynch syndrome 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 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for Lynch syndrome is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 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 which (like Lynch syndrome) 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, discussion of these issues is appropriate.

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

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Lynch syndrome 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. Mutations in four of the MMR genes can cause Lynch syndrome [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. In addition, germline deletion within EPCAM, which is not an MMR gene, can disrupt the MMR pathway. EPCAM deletions result in inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.

Genetic modifiers of cancer risk in Lynch syndrome 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 a mutation in an MMR gene.

• The p.Arg462Gly variant of 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 homozygous for the Arg462 variant and 34 years for individuals homozygous for the Gly462 variant [Kruger et al 2005].

• Pande et al [2008] evaluated a number of genes including CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 and found that two sequence variants in CYP1A1 may contribute to earlier age of colon cancer onset in individuals with Lynch syndrome.

Published Guidelines/Consensus Statements

1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available at jco.ascopubs.org. 2003. Accessed 8-5-11.
2. American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). Available at www.fascrs.org. 2003. Accessed 8-5-11.
3. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available at www.ashg.org. 1995. Accessed 8-5-11.
4. American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available at www.med.upenn.edu. 2001. Accessed 8-5-11.
5. Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing (pdf). Available at www.med.upenn.edu. 2001. Accessed 8-5-11.
6. American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available at www.acmg.net. 2000. Accessed 8-5-11.
7. National Comprehensive Cancer Network. Guidelines for colorectal cancer screening. Available at www.nccn.org. Login required. 2011.
8. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available at www.nsgc.org. 1995. Accessed 8-5-11.

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Suggested Reading

1. 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]
2. 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]

Revision History

• 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