Guidelines on Genetic Evaluation and Management of Lynch Syndrome

A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer

Francis M Giardiello MD; John I Allen; Jennifer E Axilbund; C Richard Boland; Carol A Burke; Randall W Burt; James M Church; Jason A Dominitz; David A Johnson; Tonya Kaltenbach; Theodore R Levin; David A Lieberman; Douglas J Robertson; Sapna Syngal; Douglas K Rex


Am J Gastroenterol. 2014;109(8):1159-1179. 

In This Article

Genetic Testing

Germline testing of individuals for a deleterious mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM genes has several benefits. First, it can confirm the diagnosis of LS in a patient and/or family. Second, it can determine the status of at-risk family members in pedigrees where the pathogenic mutation has been found. Third, it can direct the management of affected and unaffected individuals.

Indications for Testing

Universal Testing (Tumor Testing). As per the recommendations of the Evaluation of Genomic Application in Practice and Prevention group from the Centers for Disease Control and Prevention, discussed here, testing all patients with CRC for LS is recommended. If utilizing this strategy, most experts would recommend routine tumor-based testing on all CRCs with IHC followed by BRAF testing, if there is a lack of expression of MLH1 (Figure 2). Alternatively, the CRC can be initially tested for MSI. Universal tumor testing is likely to become the future national standard of care and is already conducted in some US hospitals. But this standard requires development of sufficient local and community infrastructure to appropriately handle genetic results before implementation as discussed. Consequently, the Multi-Society Task Force endorses testing all patients with CRC 70 years of age or younger as described here when appropriate infrastructure for testing exists. If tumor testing is done for those aged 70 years or younger only, a thorough family history is essential for those CRC patients older than 70 years; IHC and/or MSI testing should be performed for any individual whose personal and family history fulfill the Amsterdam or Bethesda guidelines or who have a ≥5% risk prediction based on the prediction models.

Figure 2.

Universal screening by tumor testing.

Traditional Testing (Selective Tumor and/or Germline Testing). Traditional indications for LS genetic testing (tumor and/or germline testing) have been developed through expert consensus by several institutions and national organizations, including the NCCN.[118–122] Genetic testing for LS is indicated for affected individuals in families meeting Amsterdam I or II criteria (Table 5) or revised Bethesda guidelines (Table 6), those with EC diagnosed at younger than 50 years old, first-degree relatives of those with known MMR/EPCAM gene mutation, and some experts would recommend individuals with >5% chance of gene mutation by computer modeling.[106]

When considering genetic testing, efforts should be made to first perform tumor testing for MSI and/or IHC in an affected relative from the family. If a tumor sample is not available, then germline testing of the MMR genes of an unaffected individual is reasonable (focusing on family members most likely to carry a mutation). Genetic testing should be offered to all at-risk relatives in families with known MMR/EPCAM gene mutations. In these cases, germline testing can be specific for the known gene mutation that causes LS in the pedigree.

Process of Genetic Testing

Genetic Counseling. Recommendations for rational use of genetic testing for cancer predisposition have been published by several groups.[123–126] They advocate pre- and post-test genetic counseling by trained health care professionals due to the clinical, psychosocial, financial, and ethical issues raised during the testing process. Of concern, a nationwide study of individuals undergoing genetic testing for hereditary CRC revealed major practitioner lapses, including failure to obtain informed consent, misinterpretation of test results (giving false-negative results), and pursuing expensive nonindicated testing.[14] The Commission on Cancer has established standards for genetics professionals, including experience and education in cancer genetics and appropriate certification.[127]

Components of the counseling session should include the collection of personal and family medical history; education about the disorder; exploration of psychosocial dimensions; informed consent, including cost and risk of genetic discrimination; disclosure of test results; and follow-up, including the ability of the patient to recontact the counselor for future discoveries pertinent to the patient's management. Details of this process can be found in Trimbath and Giardiello[128] and in the American Society of Clinical Oncology Policy Statement on Genetic Testing for Cancer Susceptibility.[127]

In the past, several barriers to patient acceptance of germline testing existed, including cost of genetic tests (exceeding $4800 in some cases) and patient concern about genetic discrimination. In recent years, improved insurance coverage and genetic laboratory preauthorization (checking insurance plan for out-of-pocket patient cost before testing) have eroded this barrier. Also, federal legislation, the Genetic Information Nondiscrimination Act of 2008, has eliminated a positive gene test as a health insurance pre-existing condition or factor for employment in most patients. However, currently, no legislation outlaws the use of this information in military personnel or in disability, long-term care, and life insurance procurement.

Universal Testing Strategy. Figure 2 outlines the pathway for universal testing.

Traditional Testing Strategy. Figure 3 reviews the indications for traditional genetic assessment and the components of genetic counseling. Figures 4,5,6 outline the pathways for traditional testing as described here.

Figure 3.

Traditional testing strategy indications and genetic counseling.

Figure 4.

Traditional testing strategy when family mutation known.

Figure 5.

Traditional testing strategy when patient is clinically affected and the family mutation is unknown.

Figure 6.

Traditional testing strategy of at-risk family member when family mutation is unknown.

Clinically Affected Members—Family Mutation Known. When the gene mutation causing LS in the pedigree is known, clinically affected patients can have site-specific germline testing to confirm the diagnosis of LS in the patient. A negative test result for the pedigree mutation in a patient with CRC would indicate that the patient does not have LS, but coincidentally developed a sporadic CRC (phenocopy) (Figure 4).

Clinically Affected Member—Family Mutation not Known. Most often patients are affected with CRC in families meeting Amsterdam criteria or Bethesda guidelines, or with other indications for genetic testing, but no LS gene mutation has been established in the pedigree. In this circumstance, if the patient's CRC tissue is available (required by federal law to be kept for 7 years after procurement), MSI and/or IHC testing can be done on tumor tissue. If microsatellite testing is stable and IHC reveals the presence of all 4 MMR proteins, then LS is essentially excluded and no additional testing is suggested. The interpretation of these results is that the patient has sporadic (noninherited) CRC. But consideration for the diagnosis of FCRCTX should be given in a patient with a family history meeting Amsterdam I criteria (Figure 5).

Conversely, if MSI testing reveals high instability or IHC testing reveals absence of 1 or more MMR proteins, then, in most circumstances, germline testing of the MMR/EPCAM genes is warranted. Specific germline testing can be guided by IHC results (see Table 8). Additional tumor testing for BRAF mutation and/or hypermethylation of the MLH1 promoter should precede genetic testing when concomitant loss of MLH1 and PMS2 proteins is noted (caused by somatic hypermethylation of the MLH1 promoter). Germline testing can result in the following possibilities: a deleterious (pathogenic) mutation of an MMR/EPCAM gene that confirms the diagnosis of LS in the patient and family; no mutation found—an inconclusive finding unless a deleterious mutation is found in other family members; and a variant of unknown significance—an inconclusive finding unless future status of the alteration is determined by the testing laboratory (a variant of unknown significance is a variation in a genetic sequence whose association with disease risk is unknown). In the latter 2 circumstances, when IHC reveals loss of MSH2, MSH6, or PMS 2 protein alone, suspicion of LS should be maintained and the diagnosis of Lynch-like syndrome entertained. When no germline mutation is found in patients with MLH1 protein loss, BRAF and MLH1 promoter testing for hypermethylation can help differentiate between patients with somatic and germline mutations. Epigenetic mutations causing LS are very rare but are characterized by MLH1 promoter methylation in both the tumor and normal tissue.

When tumor tissue of the clinically affected patient is not available, germline testing can be done. If a deleterious mutation is found, then the diagnosis of LS can be confirmed in the patient. If not, then the patient and family members should be treated as per the patient's personal and family history.

Clinically Unaffected (At-risk) Member—Family Mutation Known. Mutation-specific germline testing can be done in the at-risk member when the family mutation is known and render a dichotomous test result. If the gene mutation is found (positive), the individual has LS; if the gene mutation is not found (negative), the person does not have LS (Figure 4).

Clinically Unaffected (At-risk) Member—Family Mutation not Known. In this circumstance, first seek a clinically affected family member to genetically test to attempt to identify the family deleterious gene mutation (Figure 6). An affected family member is the most informative individual to test to find the pedigree mutation. Initially, an evaluation of the tumor is preferred to germline genetic testing if tissue is available. Once the deleterious mutation has been determined, the at-risk person can be definitively tested. If no clinically affected family member is available, germline testing of the at-risk person can be done. If a deleterious mutation is found in the unaffected member, then the diagnosis of LS is made. However, receiving results of "no mutation found" or "variant of unknown significance" are inconclusive results and no additional family genetic testing can be done.

Of note, new types of mutations or genetic alterations are continuously being reported, such as the effect of EPCAM deletions on MSH2 expression, or the rare germline epimutations of MLH1. Also, commercial laboratories doing the germline testing might lack sensitive technology for determining genetic rearrangements (in which all of the genetic components are retained), or alterations in the promoters or introns of the DNA MMR genes. Consequently, families with suspicious clinical histories and concurrent evidence of MMR deficiency through tumor testing should be counseled to undergo periodic repeated assessments as new genetic data can emerge that ultimately elucidate the underlying cause of the cancer risk in their families. In addition, the use of genetic panels might uncover patients and families with forms of attenuated polyposis, such as MYH-associated polyposis, attenuated familial adenomatous polyposis, and polymerase proofreading polyposis; there is often blurring of the clinical presentations of these syndromes and LS.