Expert Reviews full access: On the advent of MSI testing of all colorectal cancers and a substantial part of other Lynch syndrome-related neoplasms

Worldwide, more than 1 million people present with colorectal cancer (CRC) annually. Of these, 2–5% occur in the context of Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome (formerly designated as hereditary nonpolyposis CRC [HNPCC]). LS is characterized by a high lifetime risk for the development of CRC (20–70%), endometrial cancer (15–70%) and other extracolonic cancers (<15%). These extracolonic malignancies include carcinomas of the small intestine, stomach, pancreas and biliary tract, ovarium, brain, upper urinary tract and skin. .......germline mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2.

Owing to the MMR deficiency in LS tumors, a microsatellite instability (MSI) phenotype is present. MSI, however, is also found in approximately 10–13% of sporadic CRCs (in total, MSI is present in approximately 15% of all CRCs). In addition to MSI, most LS tumors lack expression in the tumor cell nuclei of one of the four MMR proteins, MLH1, MSH2, MSH6 or PMS2.

Early detection of LS is of great importance, particularly in presymptomatic mutation carriers, since colonoscopic surveillance has proven to reduce CRC morbidity and mortality by 65–70% [6] and prophylactic surgery may prevent endometrial and ovarium carcinoma effectively.

Different models and strategies have been developed to identify patients with LS. In 1990, the Amsterdam criteria I were developed to provide a basis for uniformity in collaborative studies to find the disease-causing gene. These criteria were designed to be highly specific at the expense of sensitivity. They were criticized because extra-colonic tumors were not taken into account, thereby excluding classical LS families....Therefore, the Amsterdam criteria II were established in 1999"