Original Article © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 11 | November 2013 1380 Abstract Lynch syndrome (LS) is the most common hereditary colon can- cer syndrome, and accounts for 2% to 3% of all colorectal can- cers. These tumors are caused by germline mutations of DNA mismatch repair genes, which result in microsatellite instabil- ity. Colonic and extracolonic malignancies can occur at a young age, and are often diagnosed at a late stage because of un- derrecognition of the syndrome. Identifying individuals with LS before the development of these malignancies decreases mortality because of frequent screening and surveillance of co- lonic and extracolonic cancers. Moreover, family members of these individuals can be tested and begin screening at a young age if appropriate. Classically, Amsterdam criteria and Bethes- da guidelines have been used to identify at-risk individuals; however, these tools miss a significant number of cases. As the molecular basis for LS has been clarified, more sophisticated strategies have emerged. Testing all colorectal cancers for loss of mismatch repair proteins, known as universal screening, is a strategy used to identify individuals at risk for LS. This approach has been shown to be more sensitive than previous methods that rely on family history. Implementation of universal tumor testing necessitates a systematic approach to positive results in order to have maximal effect, and could prove to be the most cost-effective approach to reducing cancer mortality in patients with LS. (JNCCN 2013;11:1380–1385) Lynch syndrome (LS), irst recognized by the charac- terization of “Family G” 1,2 and other “cancer families” 3 in the early 20th century, is a prime illustration of how identiication of familial cancer syndromes directly im- pacts individual risk stratiication. LS accounts for an es- timated 2% to 3% of all colorectal cancers (CRCs), and well-known diagnostic criteria have been established. In 1990, the International Collaborative Group on He- reditary Nonpolyposis Colorectal Cancer developed the Amsterdam criteria for the diagnosis of LS, which relied solely on family history. These criteria were modiied 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 irst-degree relative of another and exclud- ing 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 rec- ognition of LS by analyzing tumors for the characteris- tic 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-in- iltrating lymphocytes, Crohn’s-like lymphocytic reac- tion, 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 irst- or second-de- gree 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 irst- 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. From The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine and Division of Gastrointestinal Pathology, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York. Submitted February 14, 2013; accepted for publication July 23, 2013. Drs. Matloff, Lucas, and Polydorides have disclosed that they have no inancial interests, arrangements, afiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Itzkowitz has disclosed that he receives research support from and is a member of the speakers’ bureau for Exact Sciences Corporation. Correspondence: Steven H. Itzkowitz, MD, The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine and Division of Gastrointestinal Pathology, Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY 10029. E-mail: Steven.Itzkowitz@mountsinai.org Molecular Tumor Testing for Lynch Syndrome in Patients With Colorectal Cancer Jeremy Matloff, MD; Aimee Lucas, MD; Alexandros D. Polydorides, MD, PhD; and Steven H. Itzkowitz, MD