Lynch syndrome (LS), first recognized by the characterization of “Family G”1,2 and other “cancer families”3 in the early 20th century, is a prime illustration of how identification of familial cancer syndromes directly impacts individual risk stratification. LS accounts for an estimated 2% to 3% of all colorectal cancers (CRCs), and well-known diagnostic criteria have been established. In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer developed the Amsterdam criteria for the diagnosis of LS, which relied solely on family history. These criteria were modified in 1999 as the Amsterdam II criteria and are as follows: 3 or more relatives with a Lynch-associated cancer (one of whom is a first-degree relative of another and excluding familial adenomatous polyposis); Lynch-associated cancer in 2 or more generations; and at least 1 cancer diagnosed at an age younger than 50 years.
As the molecular basis of LS was elucidated, the Bethesda guidelines were developed to extend the recognition of LS by analyzing tumors for the characteristic microsatellite instability (MSI) phenotype. Bethesda criteria suggest that tumors should be tested for MSI if any of the following criteria are met: 1) CRC at an age younger than 50 years; 2) synchronous or metachronous CRC or another Lynch-associated tumor; 3) CRC with MSI-high (MSI-H) histology (presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern) if the patient is younger than 60 years; 4) CRC in a patient with at least 1 first- or second-degree relative with a Lynch-associated tumor if 1 of the tumors is diagnosed at younger than 50 years; and 5) CRC in a patient with at least 2 first- or second-degree relatives with Lynch-associated tumor, regardless of age.4 The strategies for identifying those with LS continue to evolve as appropriate cancer screening and surveillance programs are initiated for at-risk individuals.
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