Hereditary Nonpolyposis Colorectal Cancer and Lynch Syndrome

Introduction

Approximately 5% of all colorectal cancers (CRCs) are associated with a hereditary syndrome, where a germline mutation in a key tumor suppressor or DNA repair gene produces a cancer predisposition that can be inherited. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the hereditary CRC syndromes, accounting for about 3% of all CRC cases. HNPCC includes many families affected by Lynch syndrome, but overlap exists between these two terms. HNPCC is defined clinically by family history criteria, whereas Lynch syndrome is diagnosed genetically by the presence of an inherited mutation in a DNA mismatch repair (MMR) gene. Not all patients with Lynch syndrome fulfill HNPCC criteria, and not all HNPCC families have Lynch syndrome. Both syndromes confer an increased risk for colorectal and extracolonic cancers starting at an early age, and because they are both autosomal dominantly inherited, each first-degree relative of an affected person carries a 50% chance of having the disease. Physicians need to understand these syndromes to appropriately identify, diagnose, and educate affected families. Surgical decision making is based on knowledge of cancer risk, the natural history of the disease, risks of surgery, and the effects of the proposed surgery on quality of life. This chapter presents an overview of HNPCC/Lynch syndrome and provides a practical approach to its clinical management.

Historical Perspective and Clarification of Terms

In 1913, Alfred Warthin presented a large pedigree of a family in Michigan that had a predominance of colorectal and extracolonic cancers, many occurring at a young age. This report of “Family G” supported the concept that cancers can occur in families as an inherited condition and set the stage for study of inherited cancers. In 1966, Henry Lynch used the term “cancer family syndrome” in a report on two Midwestern families with an abundance of colorectal, endometrial, and gastric cancers. To distinguish this syndrome from familial adenomatous polyposis, which was the only recognized hereditary colorectal cancer syndrome at the time, the term hereditary nonpolyposis colorectal cancer (HNPCC) was introduced. HNPCC was defined by clinical criteria to facilitate research into the syndrome. The Amsterdam criteria were established in 1991 by the International Collaborative Group on HNPCC ( Table 59-1 ). In 1999, the Amsterdam criteria were revised to include extracolonic cancers as qualifying criteria, and these Amsterdam II criteria have become the way to define HNPCC (see Table 59-1 ).

In 1993, germline mutations in DNA MMR genes were found to be the genetic cause of HNPCC in many families. However, it became apparent that only about 60% of HNPCC families carry a germline MMR gene mutation. These genetically defined patients are diagnosed as having Lynch syndrome. Only about 80% of Lynch syndrome families fit the Amsterdam criteria, and thus at least 20% of cases are missed with reliance on these criteria to screen for Lynch syndrome. In families that fulfill the Amsterdam II criteria, the suspicion of Lynch syndrome is raised and genetic counseling and testing are indicated; however, Amsterdam II criteria in themselves do not define Lynch syndrome. That is a genetic definition. Patients from families who meet Amsterdam criteria but have microsatellite stable tumors (i.e., intact MMR) have familial colorectal cancer type X (FCC X), which carries a lower cancer risk than does Lynch syndrome. This distinction is important for appropriate clinical management. When discussing Lynch syndrome and HNPCC, it is important to use the correct definitions to allow for the proper classifications of the different phenotypes and genotypes.

Genetic and Molecular Cause of Lynch Syndrome

Lynch syndrome is caused by inactivation of one of four DNA mismatch repair genes: MLH1, MSH2, MSH6, or PMS2 . These genes encode proteins that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to recognize and repair nucleotide mismatches that occur during DNA replication. Approximately 90% of Lynch syndrome cases are caused by an inherited mutation in MLH1 or MSH2 . Rarely, Lynch syndrome can also result from an inherited deletion in the EPCAM gene, which silences expression of MSH2 . Inherited germline hypermethylation of MLH1 , resulting in silencing of its expression, has also been reported but is very rare.

Lynch syndrome is inherited in an autosomal-dominant pattern. When a child inherits the mutated allele from the affected parent, normal MMR function is maintained by the wild-type allele inherited from the unaffected parent. However, with sporadic loss of the wild-type allele, MMR function is lost. Because DNA mismatch errors tend to occur in areas of repeating nucleotide bases called microsatellites, unrepaired errors accumulate in these regions and lead to microsatellite instability in tumors. Panels of microsatellite markers have been established to assess tumor DNA microsatellite stability, the most common of which includes five markers. If two or more are unstable, the tumor is considered microsatellite instability high (MSI-H)—evidence of DNA MMR deficiency. About 90% of all Lynch syndrome tumors are MSI-H. In contrast, about 15% of sporadic colorectal tumors are MSI-H, resulting from epigenetic loss of MLH1 via DNA promoter hypermethylation.

Histologic Features of Lynch Tumors

Colorectal cancers arising within Lynch syndrome have distinct histologic characteristics that, when recognized in a tumor, suggest defective MMR. These characteristics include the presence of tumor-infiltrating lymphocytes, a Crohn-like lymphoid reaction, signet ring cells, mucinous components, and a lack of dirty necrosis. Some of these histologic factors have been incorporated into the revised Bethesda criteria ( Box 59-1 ) as a tool to identify which patients should undergo testing for the presence of MSI ( Figs. 59-1, 59-2, and 59-3 .)

Diagnosing Lynch Syndrome

The first step in managing Lynch syndrome in a family is to diagnose it. Several strategies can be used to select patients for genetic testing, including clinical criteria, prediction models, and tumor testing.

Tumor Testing

For patients who have a cancer or a large adenoma, tumor testing for MMR deficiency is a more accurate and cost-effective way of identifying potential patients with Lynch syndrome than are clinical criteria or prediction models alone. MMR deficiency is evaluated by MSI or by immunohistochemistry for expression of MMR proteins. About 90% of Lynch syndrome CRCs will be MSI-H and lack MMR protein expression. Lack of expression of a specific protein can direct germline testing for mutations to a specific gene. If MSH2 is mutated, both MSH2 and MSH6 are lost; if MSH6 is mutated, only MSH6 is lost. If MLH1 is mutated, both MLH1 and PMS2 expression are lost, but if PMS2 is mutated, then only PMS2 is lost. Depending on the findings of immunohistochemistry, the appropriate gene(s) is/are sequenced. About 15% to 18% of all colorectal cancers are MSI-H, and approximately 85% of these are attributable to acquired methylation of the MLH1 promoter not associated with Lynch syndrome. Therefore, if MLH1 expression is lost, results should be taken within the context of age and family history. Most tumors with methylation of MLH1 will have mutations in BRAF , whereas these are almost never found in Lynch tumors. Therefore, testing for BRAF mutations and MLH1 methylation can differentiate most tumors with absent MLH1 expression into Lynch syndrome and not Lynch syndrome.

Although tumor testing is the best way to identify patients for genetic testing, selection criteria for testing are debated. Limiting tumor testing by age or clinical criteria would lead to a significant number of Lynch syndrome cases being missed, and thus there is a move toward testing of all resected CRCs. In 2009, the Evaluation of Genomic Applications in Practice and Prevention Working Group recommended that samples of all newly diagnosed CRC undergo MSI and/or immunohistochemistry for MMR protein expression. These guidelines are endorsed by the Collaborative Group of the Americas on Inherited Colorectal Cancer. Recently, the National Comprehensive Cancer Network recommended universal screening of all colorectal cancers for persons younger than 70 years and for those older than 70 years who meet revised Bethesda guidelines. The Cleveland Clinic approach to universal tumor testing is summarized in Figure 59-4 .

Ideally, tumor testing is performed using the colonoscopic biopsy specimen taken at the time of diagnosis, before surgery. This testing allows preoperative identification of Lynch syndrome and affords an opportunity for patient education and a more informed choice regarding surgical strategy.

Genetic Counseling and Testing

Identification of a specific mutation as the underlying cause of Lynch syndrome benefits the patient in terms of personalized risk assessment and facilitates testing of at-risk family members. Indications for referral to a genetic counselor are listed in Box 59-2 . For patients with a diagnosis of cancer, genetic counseling and testing should be initiated at the time of diagnosis. Working with the clinician, the genetic counselor uses tumor test results to guide which gene should be sequenced. Germline genetic testing is most commonly conducted with a blood sample but also may be conducted with material from a buccal swab. When tumor testing is not available to suggest the particular gene for testing, other strategies are employed. Some counselors sequence all four MMR genes, and recently, commercial gene panel tests have become available for patients with suggestive phenotypes. The use of a panel of 18 to 25 genes promises to reveal unsuspected germline mutations in patients with atypical clinical presentations, which may lead to quandaries in management. Because of the complexity of interpreting results, genetic testing should be performed within the context of appropriate patient education and counseling both before and after testing. For at-risk relatives of a person with Lynch syndrome, testing should be considered around the age when cancer surveillance would commence. These patients can be screened for the family mutation, which is a much cheaper and easier process than finding the mutation in the first place.