Genetic Testing for Lynch Syndrome

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for Genetic Testing for Lynch Syndrome. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for Genetic Testing for Lynch Syndrome and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site. 

Internet Only Manual (IOM) Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
• Chapter 15, Section 80.1 Clinical Laboratory Services 
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
• Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD 

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury. 
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations. 
• Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.

Federal Register References:

Code of Federal Regulations (CFR), Title 42, Volume 2, Chapter IV, Part 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

History/Background and/or General Information

I. Lynch Syndrome (LS)

This local coverage determination limits Lynch syndrome (LS) genetic testing to a stepped approach for Microsatellite Instability and Immunohistochemistry (MSI/IHC) screening, BRAF gene mutation, MLH1 gene promoter hypermethylation and targeted mismatch repair (MMR) germ-line gene testing to patients suspected of having LS.

Most colorectal cancer is caused by non hereditary somatic mutations. Individuals with LS (aka Hereditary nonpolyposis colorectal cancer (HNPCC) are predisposed to cancer due to having inherited or de novo germ-line mutations in DNA repair genes, that result in an accelerated accumulation of somatic mutations. LS, the most common hereditary cause of colorectal cancer, accounts for 2-3% of all colorectal cancers, followed by familial adenomatous polyposis (FAP) which accounts for <1% of colorectal malignancies and MUTYH-associated polyposis (MAP) whose frequency of occurrence is very rare.

LS is an autosomal dominant familial cancer syndrome caused by mutations in multiple susceptibility genes (e.g., MLH1, MSH2, MSH6, PMS2, EPCAM), and is associated with an increased lifetime risk for colorectal cancer (CRC) and other malignancies within the tumor spectrum including at least endometrial, ovarian, gastric, small bowel, urothelial, hepatobiliary tract, sebaceous and pancreatic cancers. Current literature suggests LS annually affects 28,000 individuals. In individuals with LS, the lifetime risk of colon cancer may be as high as 75% by the age of 70 years, with an average age onset of 45 years in MLH1 and MSH2 mutation carriers. While the incidence of adenomas in individuals with LS is similar to that in the general population, the high rate of colorectal cancer is due to an acceleration of the adenoma to carcinoma sequence.

Cancer risks associated with LS are largely derived from family studies. Mutations in MLH1 and MSH2 account for 70-90% of families with LS. The risk of colon and endometrial cancer is less in MSH6 and PMS2 mutation carriers, although the cancer risk may not be lower for MSH6 carriers if one takes the data out to age 80. While individuals with a single MLH1, MSH2, MSH6 and PMS2 mutation develop cancers in mid-life, individuals with biallelic MLH1, MSH2, MSH6 and PMS2 mutations have a distinctive phenotype and tumor spectrum, and often develop cancer as early as the first decade of life.

First-degree relatives of mutation carriers have a 50% probability of having the same germ-line mutation. Despite the high penetrance of CRC and endometrial cancer and recommendations of consideration for screening unaffected first-degree relatives following diagnosis of an LS proband, testing of genetic carriers who are unaffected with a Lynch related cancer is not a benefit, and is statutorily excluded from coverage.

II. Testing Strategy for Patients with Personal History of Colorectal Cancer

Step 1: Patient selection

Patients with colorectal and/or endometrial cancer suspected of LS must undergo a comprehensive review of physical findings and a complete personal and family history.

In 1989, the Amsterdam criteria defined what is known as Hereditary Non-polyposis Colon Cancer Syndrome, and in 1999, the criteria were revised to include extra-colonic tumors (Table 1). Today we know there are two distinct groups comprising HNPCC: those with hereditary DNA mismatch repair germ-line mutations, known as Lynch Syndrome, and those with normal DNA mismatch repair, known as Familial Colorectal Cancer Type X.

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Table 1. Amsterdam Criteria II (ACII)
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There should be at least three relatives with CRC or with a Lynch syndrome-associated cancer: endometrial, small bowel, ureter or renal pelvis cancer.

• One relative should be a 1st-degree relative of the other two,
• At least two successive generations should be affected,
• At least one tumor should be diagnosed before age 50 years,
• FAP should be excluded in the CRC case, if any,
• Tumors should be verified by histopathological exam

Approximately 50% of families meeting the ACII criteria have a mutation in an MMR gene. However, these criteria are very stringent and miss as many as 68% of patients with LS.

In 1997, the Bethesda guidelines were developed to identify individuals with CRC who should be tested for MSI. In 2002, the guidelines were revised (Table 2) to clarify selection criteria for microsatellite instability (MSI) testing and mismatch repair (MMR) protein expression by immunohistochemistry (IHC). Screening tumors of patients meeting the Bethesda guidelines for MSI was shown to be cost-effective with newly diagnosed CRC.

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Table 2 - Revised Bethesda Guidelines
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Meeting any of the following are sufficient for consideration of MSI/IHC testing

• CRC diagnosed under age 50
• Presence of synchronous, or metachronous CRC or other Lynch-associated tumor, regardless of age
• CRC with MSI-H histology diagnosed in an individual who is < age 60
• CRC diagnosed with one or more 1st-degree relatives with a Lynch-related tumor, with one of the cancers diagnosed under age 50
• CRC diagnosed in two or more 1st- or 2nd-degree relatives with a Lynch-related tumor, regardless of age

If a patient meets standards for LS testing in Step 1 (i.e., meets ACII or Revised Bethesda guidelines), the physician should proceed to Step 2 and 3.

Step 2: Immunohistochemistry (IHC) testing for LS Screening

The use of IHC to detect loss of DNA mismatched repair (MMR) protein expression complements MSI to screen patients for defective MMR (DMMR), including both sporadic dMMR and LS dMMR. IHC allows detection of loss of protein expression for the MLH1, MSH2, MSH6 and PMS2 genes. Loss of MMR protein expression is detected by the absence of nuclear staining in the tumor cells and the presence of nuclear staining in lymphocytes and normal colon crypt epithelial cells.

The MMR proteins are present as heterodimers (MLH1 pairs with PMS2, and MSH2 pairs with MSH6). Knowledge of MMR protein expression loss patterns allows a logical and cost effective “directed” testing appropriate for germ-line mutation analysis. As a general rule, loss of expression of MLH1 or MSH2 is associated with loss of their partners. For example, mutation of the MLH1 gene generally leads to loss of expression of both the MLH1 and PMS2 proteins. However, loss of PMS2 or MSH6 due to a germ-line mutation is associated only with loss of the mutated protein. For example, mutation of the PMS2 gene leads to loss of expression of only the PMS2 protein.

If IHC is done first and is abnormal, MSI testing is not warranted. Often IHC is done first because of its rapid turn-around and minimal amount of tissue required. If IHC demonstrates loss of protein expression for the MLH1, MSH2, MSH6 and PMS2 genes, the following test results direct further testing:

• MLH1 loss by IHC, test for BRAF gene mutation (Step 4) or test for MLH1 promoter, (Step 5)
• MSH2/MS6 loss by IHC, perform MSH2 germ-line testing (Step 6)

If IHC test results are normal, there remains a small chance of high levels of microsatellite instability (MSI-H), so both IHC and MSI would be needed to rule out LS in a clinically suspicious setting.

Step 3: Microsatellite Instability (MSI) Analysis for LS Screening

MSI analysis for screening LS microsatellites are short repeated segments of DNA spread throughout the genome. Under normal conditions, the MMR gene complex (MLH1, MSH2, MSH6 and PMS2 genes) corrects mismatched base pairs that occur during the final stage of DNA replication. When the MMR complex is functioning normally, all cells show an identical pattern of microsatellite lengths. When the MMR complex is non-functioning, due to two hits of any type, random mutations accumulate in microsatellites, leading to differences in microsatellite lengths (microsatellite instability, MSI). Therefore, MSI indicates loss-of-function defects in a MMR protein, which may be due to somatic mutations, germ-line MMR gene mutations, allelic loss, or to epigenetic down-regulation. MSI is usually associated with absence of protein expression of one or more of the MMR proteins (MLH1, MSH2, MSH6 and PMS2).

DNA from paraffin-embedded tumor tissue and normal tissue or peripheral blood is used for MSI analysis. A microsatellite is considered unstable if the distribution of the tumor fragments differs from that of the normal tissue. Noncancerous tissue in individuals with LS does not show MSI because normal tissue is heterozygous for the germ-line mutation.

Levels of MSI in colon tumors are classified as:

• MSI-H - >30% or more of a tumor’s markers are unstable;
• MSI-L - > one but < 30% of a tumor’s markers are unstable;
• MSS - no loci are unstable.

MSI-L and MSS indicates the MMR mechanism is functioning adequately. Virtually all CRC tumors from individuals with LS demonstrate MSI-H. However, MSI-H is NOT diagnostic of LS as MSI-H can be observed in roughly 15% of sporadic colorectal cancers. In other Lynch tumors, the % level of MSI-H is less consistent and is inadequately studied.

As indicated above, MSI testing is not necessary if IHC demonstrates loss of protein expression for the MLH1, MSH2, MSH6 and PMS2 genes. If IHC test results are normal, there remains a small chance of high levels of microsatellite instability (MSI-H), so both IHC and MSI should be performed to rule out LS in a clinically suspicious setting such as meeting a Revised Bethesda guideline. Additionally, some individuals with MSH6 germ-line mutations do not manifest the MSI-H phenotype. This finding supports the diagnostic strategy to screen suspected LS patients with CRC by both MSI and IHC. Immunohistochemistry (IHC) can be used to identify whether the protein products of MLH1, MSH2, MSH6 and PMS2 genes are present or absent. Individuals with tumors that display high levels of MSI or loss of expression of MMR proteins by IHC are then referred for targeted germ-line mutation.

Steps 4 and/or 5 apply only for tumors that are negative for MLH1 protein expression by IHC.

Step 4: BRAF V600E (BRAF) Mutation Testing 

BRAF mutation testing and MLH1 promoter methylation studies distinguish between sporadic dMMR and LS dMMR. This is because BRAFM mutation and MLH1 PHM are very seldom seen in LS. BRAF mutation testing of the CRC tumor is associated with the presence of an epigenetic alteration (i.e., hypermethylation of MLH1) and either finding excludes germ-line MMR gene mutation (e.g., LS).

Step 5: MLH1 Promoter Hypermethylation (MLH1 PHM)

The combination of MLH1 PHM and a BRAF mutation in tumors rules out LS and no further molecular analysis is warranted. Tumors with MLH1 PMH identify dMMR which will most often be sporadic, but its presence does not fully rule out LS. However, there have been rare reports of MLH1 hypermethylation as a second hit in LS and there are new reports of constitutional MLH1 methylation. As a rule, discovery of MLH1 PHM indicates the tumor is not due to Lynch syndrome.

The following combinations of BRAF and MLH1 promoter methylation test results direct further testing in individuals with CRCs with loss of IHC expression of MLH1/PMS2:

• If BRAF mutation is present, no further testing is medically necessary; LS is ruled out.
• If BRAF mutation is absent, MLH1 promoter methylation testing is indicated and directs the following testing:
  • If MLH1 is hypermethylated, germline MLH1 is not medically necessary.
  • If the MLH1 promoter is hypermethylated and ACII if fulfilled, germ-line MLH1 may still be considered (2nd hit scenario). 
  • IF the MLH1 promoter is normally methylated, and BRAF is negative for mutation then germ-line MLH1 testing is medically indicated. 

Note: There is variability in laboratory preference for BRAF and MLH1 promoter testing sequence. Although BRAF is generally cheaper and faster, some labs test MLH1 PHM first because it is more sensitive for detection of sporadic dMMR.

In a study by Gausachs (2012), when MLH1 PHM testing is used in conjunction with BRAF mutation testing, the cost per additional mutation detected when using hypermethylation analysis was lower than that of BRAF and germinal MLH1 mutation analysis. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germ-line analysis when LS is suspected and MLH1 protein expression is absent.

Step 6: Targeted MMR (MLH1, MSH2, MSH6 and PMS2 gene) Germ-line and EpCAM Testing

Step 6A: MLH1 Testing

When IHC shows loss of both MLH1 and PMS2, further genetic testing of PMS2 is not indicated, as no cases have been reported of a PMS2 germ-line mutation when IHC showed a loss of both MLH1 and PMS2. PMS2 mutations have only been detected when IHC shows a loss of PMS2 only. If MLH1 gene mutation germ-line is positively identified, then LS is diagnosed and further testing of the patient is not medically necessary.

Step 6B: MSH2 Testing

When IHC shows loss of MSH2 and MSH6, genetic testing should start with analysis of the MSH2 gene, given its frequency of germ-line mutation in LS. If MSH2 germ-line mutation is identified, then LS is diagnosed, and further testing of the patient is not medically necessary.

However, if genetic testing for germ-line mutations in MSH2 is negative, analysis for deletion in the EpCAM gene should be performed (Step 7). If EpCAM is also negative, genetic testing of MSH6 should be performed (Step 6C). The presence of MSI and the loss of MSH2/MSH6 strongly indicate a MMR germ-line defect.

Step 6C: MSH6 Testing

When IHC shows loss of just MSH6, it suggests a germ-line mutation in MSH6 and genetic testing of that gene is indicated. As previously noted, MSH6 CRC tumors can be MSI-H, MSI-L or MSS. This pitfall illustrates the utility of IHC for MMR protein expression. If MSH6 germ-line mutation is identified, then LS is diagnosed, and further testing of the patient is not medically necessary.

Step 6D: PMS2 Testing

If IHC shows PMS2 loss only, germ-line testing for PMS2 mutations is indicated. No cases of a PMS2 germ-line mutation have been identified after IHC showed a loss of both MLH1 and PMS2. If PMS2 germ-line mutation is identified, then LS is diagnosed, and further testing of the patient is not medically necessary.

Step 7: EpCAM Testing

Recently, deletions in a portion of the EpCAM gene were found in a subset of families with LS with a loss of MSH2 by IHC. A common deletion in the 3’ region of EpCAM causes somatic hypermethylation of MSH2, as the 2 genes are adjacent to one another on chromosome 2. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC, but without MSH2 or MSH6 mutation, will have germ-line deletions in EpCAM. Early estimates suggest that germ-line mutations in EpCAM may account for approximately 6% of LS cases and possibly as high as 30% when IHC shows a loss of MSH2.

Note: Many labs incorporate EpCAM detection their MSH2 dup/deletion analysis. 

Covered Indications

IHC and/or MSI Testing

LS tumor screening with IHC or MSI on colorectal and/or endometrial tumors is considered medically necessary and covered for the following indications: 

• All Individuals with colorectal cancer diagnosed at ≤70 years of age, and those >70 years of age who meet the revised Bethesda guidelines**, OR 
• Individuals with endometrial cancer.

For coverage, the treating physician/pathologist is expected to follow the stepped approach outlined for LS screening and targeted MMR testing in this policy. Germ-line testing includes sequence and duplication-deletion analysis for a given gene.

MMR Germline Gene Mutation Testing Exception

If a lab is unable to perform the stepped testing approach outlined in this LCD, multiple germ-line gene testing will be covered only for one or more of the following findings:

• MSI/IHC testing yields normal IHC and MSI-H, suggesting LS 
• If tumor is not available or determined by a pathologist to be inadequate to assess DNA MMR deficiency by MSI or IHC, then MMR germ-line testing can be conducted on blood if the individual fulfills the ACII or revised Bethesda guidelines. 
• CRC tumor diagnosis prior to eligibility AND tumor sample no longer available AND individual meets ACII or revised Bethesda guidelines or was diagnosed with endometrial cancer before 50

If targeted gene testing is not possible, MLH1 and MSH2 testing should be performed first, since these two genes account for the majority of germ-line mutations. If no mutation is identified in MLH1 or MSH2, testing of MSH6 is indicated. If no mutation is identified in MSH6, testing of PMS2 may be considered.

Testing for Known Familial Variant

Testing for a specific known familial variant is considered medically necessary and covered only when the individual being tested has signs and symptoms of a Lynch-associated cancer AND has a blood relative with the specific disease-causing mutation for LS.

Note: This LCD does not imply that testing family members of a known familial variant is not medically warranted. The scope of the benefit requires the beneficiary to have signs and symptoms of disease. Coverage of molecular testing for LS for carrier status or family studies is considered screening and is statutorily excluded from coverage. 

Limitations

Universal Testing for CRC and Endometrial Cancer

Universal testing of CRC and endometrial cancers by MSI/MMR protein expression by IHC is not a benefit. The NCCN colorectal cancer screening guidelines (V2.2013) recommends that “risk assessment be individualized and include a careful family history … and if a patient meets the criteria for an inherited colorectal syndrome, further risk evaluation and counseling, as outlined in the guidelines, is required. The guidelines indicates that “when any one of the revised Bethesda criteria are met, the possibility of LS is suggested, and IHC staining for the four MMR proteins and/or MSI testing on the colon tumor of the youngest affected family member is warranted.”

The NCCN colon cancer treatment guidelines (V3.2013) “recommend that MMR protein testing be performed for all patients younger than 50 years with colon cancer, based on an increased likelihood of LS in this population. MMR testing should also be considered in all patients with stage II disease, because stage II MSI-H patients may have a good prognosis and stage II MSI-H patients do not benefit from 5-FU adjuvant therapy.”

Similarly, although the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence in 2009 to recommendation offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives, molecular testing for LS for identify carrier status or family studies is not a benefit.

The ordering/treating physician or pathologist is expected to obtain sufficient clinical and family history to warrant first-line testing (IHC/MSI), and subsequent targeted MMR germ-line testing or for germ-line mutation exceptions (as above). The clinical/family data to support IHC/MSI testing should be documented in the test interpretation/report and the information should be available to the lab performing targeted testing to assist the lab in the appropriate selection of target genes. Labs performing MMR germ-line panels without appropriate selection of targeted genes based on patient data, screening test (MSI/IHC) results, or exceptions are not reasonable and necessary. 

At the current time, there is insufficient data to warrant MMR testing for prostate cancer, even though preliminary studies suggest that prostate cancer in MMR gene mutation carriers share a molecular profile and at least one pathological feature in common with other LS-associated tumors. Similarly the clinical significance of MMR testing in other malignancies is not known. Therefore, molecular testing for malignancies other than those specifically cited in this LCD is non-covered. 

As published in the CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13, Section 13.5.4, an item or service may be covered by a contractor LCD if it is reasonable and necessary under the Social Security Act Section 1862 (a)(1)(A). Contractors shall determine and describe the circumstances under which the item or service is considered reasonable and necessary.

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Documentation Requirements

Please refer to the Local Coverage Article: Billing and Coding: Genetic Testing for Lynch Syndrome (A57450) for documentation requirements that apply to the reasonable and necessary provisions outlined in this LCD.

Utilization Guidelines

Please refer to the Local Coverage Article: Billing and Coding: Genetic Testing for Lynch Syndrome (A57450) for utilization guidelines that apply to the reasonable and necessary provisions outlined in this LCD.

First Coast Service Options, Inc. reference LCD number(s) – L34483

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3. Bouzourene H, Hutter P, Losi L, Martin P, Behattar J. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9(2);167-72. doi: 10.1007/s10689-009-9302-4.

4. Center for Disease Control and Prevention. Genetic Testing. Health Professionals: More about Genetic Testing for Lynch Syndrome. (2011, April 26).

5. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidit and mortality from Lynch syndromes in relatives. Genetic in Med. Jan 2009;11(1):35-41.

6. Gausachs M, Mur P, Corral J,et al. MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: A cost-effectiveness study. European Journal of Human Genetics. 2012;20:762-8.

7. Grover S, Stoffel EM, Mercado RC, Ford BM, Kohlman WK, Shannon KM, et al. Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome. J Clin Oncol. 27(24):3981-6.

8. Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, et al. Heritable Somatic Methylation and Inactivation of MSH2 in Families with Lynch Syndrome due to Deletion of the 3’ exons of TACSTD1. Nat Genet. Jan 2009;41:112-7.

9. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med, 2003;348(10):919-2.

10. Lynch HT, Lynch PM, Lanspa SJ, Synder CL, Lynch JF, Boland CR. Review of the Lynch Syndrome: History, Molecular Genetics, Screening, Differential Diagnosis, and Medicolegal Ramifications. Clin Genet. 2009;76:1-18.

11. National Comprehensive Cancer Network®. NCCN Guidelines Colorectal Cancer Screening. Version 2.2013

12. National Comprehensive Cancer Network®. NCCN Guidelines Colon Cancer. Version 3.2013.

13. Palmetto, GBA Future LCD (L33779). Genetic Testing for Lynch Syndrome. Effective November 04, 2013.

14. Quehenberger F, Vasen HFA, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. 2005;42:491-496.

15. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer. NEJM. Jul 2003;349:247-57.

16. Rumilla K, Schowalter KV, Lindor NM, Thomas BC, Mensink KA, Gallinger S, et al. Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases. J Mol Diagn. Jan 2011;13(1):93-9.

17. Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD,et al. The Clinical Phenotype of Lynch Syndrome Due to Germline PMS2 Mutations. Gastroenterology. 2008;135:419-28.

18. Strafford JC. Genetic testing for lynch syndrome, an inherited cancer of the bowel, endometrium, and ovary. Rev Obstet Gynecol. 2012;5(1):42-9.

19. Thomas BC,Ferber MJ, Lindor NM. DNA Mismatch Repair and Lynch Syndrome. In: Potter JD, Lindor NM, eds. Genetics of Colorectal Cancer. New York, NY:Springer Science; 2009.

20. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Natl Cancer Inst. 2004;96:261-8.

21. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. May 1991;34(5):424-5.

22. Vasen HF, Moslein G, Alonso A. Guidelines for the Clinical Management of Lynch Syndrome (hereditary non-polyposis cancer) J Med Genet. 2007;44:353-62.

23. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch)

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